bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-08-02: Gene expression changes in methylnitrosourea (MNU)-induced ER+ mammary cancers following short-term treatment of rats with SERMs (Tamoxifen and Arzoxifene)
Authors: Lubet R , Vedell P , Grubbs C , Bernard P , You M
Published: August 2014

SERMs have proven to be highly effective in both therapy and prevention of ER+ breast cancers. Tamoxifen has been the most commonly used SERM, but arzoxifene (another high- affinity competitive SERM agonist) showed strong activity in early clinical trials against ER+ breast cancer; although further development was discontinued. Both SERMs have shown a dose dependent effect on prevention and therapy of rat mammary tumors in the ER+ MNU model of cancer. Of interest, the doses required for prevention was significantly lower than the doses required for therapy. In the present study, rats bearing mammary cancers induced by MNU were treated with tamoxifen (0.66, 3.3, 20 and 100 ppm in diet) or arzoxifene (3.0 ppm in diet) for 5 days. Global gene expression analysis showed that more than 100 genes were down-regulated and more than 100 genes were up-regulated (p < 0.05 and fold change >1.5) in cancers treated with tamoxifen doses > 3 ppm; and that many of these gene changes were dose dependent. The genes modulated by tamoxifen and arzoxifene were enriched in the cell cycle pathway that were related to chromosome condensation in prometaphase [including Aurora-A, Aurora-B, Bub1B, non-SMC condensing I complex, subunit H (BRRN1), Condensin, CAP-G, CAP-G/G2, CAP-H/H2, CAP-D2/D3, CAP-E, TOP2, Cyclin A, Cyclin B, CDK1, Histone H1 and inter-centromere protein (INCENP]. Employing a different set of tamoxifen treated samples, we were able to confirm that many of the same genes were modulated employing a quantitative RT-PCR assay. Finally, we will compare certain of the gene changes obtained in the animal model with gene changes observed in human neoadjuvant trials.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-08-02.
Abstract P1-09-01: Long-term effect of tamoxifen use on the risk of contralateral breast cancer
Authors: Mellemkjær L , Steding-Jessen M , Frederiksen K , Andersson M , Olsen JH
Published: August 2014

Background: Tamoxifen has been used widely in the treatment of breast cancer due to its beneficial effects on recurrences and mortality. Both randomized trials and observational studies give evidence that tamoxifen also reduces the incidence of contralateral breast cancer. The effect of tamoxifen seems to be present not only during treatment but also after termination of treatment, but the question is how long this effect lasts. Few studies have presented long-term follow-up data on risk of contralateral breast cancer after tamoxifen treatment.

Material and Methods: In the Danish Breast Cancer Cooperative Group (DBCG) Database, we identified 50,323 women who had undergone surgery for invasive breast cancer and who had received treatment according to DBCG guidelines during 1978–2007. Among these women, 16,319 were users of tamoxifen while 34,004 were non-users. Contralateral breast cancer cases were identified in the Danish Cancer Registry and in the DBCG Database through 2009. The incidence of contralateral breast cancer among users of tamoxifen was compared to that of non-users by estimating incidence rate ratios (IRRs) in Cox regression analyses with adjustment for age at first breast cancer diagnosis, calendar period at first breast cancer diagnosis, histology of first breast cancer, radiotherapy, chemotherapy and other endocrine treatments besides tamoxifen.

Results: During follow-up, 295 cases of contralateral breast cancer were observed among users of tamoxifen while 1,485 cases were observed among non-users resulting in an IRR of 0.82 (95% CI = 0.71–0.94) after adjustments. Further analyses will include calculation of IRRs for contralateral breast cancer by time since breast cancer diagnosis, duration of tamoxifen and time since cessation of tamoxifen as well as calculation of IRRs after restriction to estrogen receptor positive breast cancer patients. Results of these analyses will be presented.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-09-01.
Abstract P1-10-02: Comparative Preventive Efficacy of Select Chinese Herbs in Breast Carcinoma Derived Isogenic Cells with Modulated Estrogen Receptor Functions
Authors: Telang NT , Li G , Katdare M , Sepkovic DW , Bradlow HL , Wong GYC
Published: August 2014

Background: Human mammary carcinoma derived estrogen receptor positive (ER+) MCF-7 cells depend on 17β-estradiol (E2) for cellular proliferation in vitro and for tumor development in vivo. Traditionally, ER functions as a ligand activated nuclear transcription factor with E2 as its physiological ligand, and limited availability of E2 modulates ER functions. We have recently demonstrated preventive efficacy of selected Chinese nutritional herbs in this MCF-7 cell culture model. The present study screened additional Chinese nutritional herbs for their preferential preventive efficacy on MCF-7 cells with modulated ER functions.

Methods: MCF-7 cells were maintained in medium supplemented with either 0.7% serum, <1 nM E2, or 0.7% serum+20 nM E2. This approach, while preserving the MCF-7 genotype, provides isogenic cells with either non-functional ER (ER-NF) or functional ER (ER-F) phenotype, and thereby, enables paired comparisons for the preventive efficacy of herbs on the two phenotypes. Anchorage dependent and anchorage independent growth, cell cycle progression, cellular apoptosis, and E2 metabolism represent the quantitative end points.Results: Long-term maintenance of MCF-7 cells in a serum-depleted culture medium (0.7% serum, < 1 nM E2) selects a proliferative sub-population of E2 responsive cells with transiently non-functional ER due to limited availability of E2. The growth inhibitory effects of non-fractionated aqueous extracts from 15 Chinese nutritional herbs were compared in MCF-7 cells selected for either the ER-NF or the ER-F phenotype. Comparative dose response experiments identified IC50 concentrations, and thereby, facilitated rank ordering for growth inhibition. Although all the herbs tested were effective in the present model, two herbs exhibited greater efficacy for the ER-NF phenotype, eight herbs exhibited greater efficacy for the ER-F phenotype, while five herbs exhibited equal efficacy for both the ER-NF and the ER-F phenotypes. Representative herbs at their respective maximum cytostatic concentrations from these three groups, inhibited anchorage independent growth, induced G1 arrest, induced apoptosis, and regulated E2 metabolism in favor of the anti-proliferative metabolites 2-hydroxyestrone and estriol.

Conclusions: Preferential growth inhibition by Chinese nutritional herbs in isogenic ER-NF and ER-F phenotypes of MCF-7 cells and mechanistic efficacy of representative herbs identify possible leads towards their rapid prioritization for planning prevention trials on ER+ and ER− clinical breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-10-02.
Abstract P1-12-03: Low-dose capecitabine monotherapy in HER-2 negative metastatic breast cancer: a retrospective study.
Authors: Ambros T , Zeichner SB , Zaravinos J , Montero AJ , Ahn E , Mani A , Kronish L , Mahtani RL , Vogel CL
Published: August 2014

Background: Capecitabine (CAPE) has clinical activity in metastatic breast cancer (MBC) at an FDA approved dose of 1,250mg/m2 twice daily for 14 days every 21 days (BID Q14). This schedule has been adopted by many United States oncologists, although the starting dose is often reduced. To determine if lower doses of CAPE have comparable clinical activity as the FDA approved dose, we performed a retrospective analysis.

Methods: A retrospective review of records from a large breast cancer oncology practice and from Sylvester Cancer Center Deerfield Beach from 2000–2008 was performed after approval of the University of Miami IRB. Standard practice was CAPE low dose (CAPE-L) 1,000mg BID Q14. Primary outcome was clinical benefit rate (CBR) defined as complete response (CR), partial response (PR) or stable disease (SD) lasting for ≥ 6 months. Response rates (RR) in patients with measurable disease, progression free survival (PFS), overall survival (OS) defined as time period between beginning of CAPE and death, and adverse events (AE) defined according to the NCI CTCAE version 3.0 were secondary endpoints. A literature review was performed for comparison.

Results: Data from 296 patients (pts) with HER-2 negative MBC were reviewed. Of those, 73 received CAPE-L at a starting dose between 303 mg/m2 and 965 mg/m2 (median 614 mg/m2) BID Q14. Median number of prior lines of therapy was 1 (range 0–10); 34/73 (46.6%) of pts received CAPE-L as first line therapy. 23.3% of pts required dose reductions because of palmar-plantar erythrodysesthesia (PPE) (44%), diarrhea (17%), mucositis (11%) or other (28%). RR in 61 patients with measurable disease was 25%. PR occurred in 16/73 (22%), CR (0%), SD ≥ 6 months 21/73 (29%), and PD 31/73 (43%), with a CBR of 37/73 (51%). Median PFS and OS were 6.2 months (95% CI, 4.4 to 8) and 21.4 months (95% CI, 14.4 to 28.6), respectively. AEs are reported in table 2. We recognized 12 trials that used the FDA approved dose in 1,949 patients. Bidimensionally measurable disease was present in 1,630 patients. CBR was reported as 62% in 1,006 patients and RR as 24% in 398. Weighted averages of median PFS and OS were 5.1 months (95% CI, 4.5 to 5.7) and 12 months (95% CI, 9.6 to 14.4), respectively. Detailed toxicity data were available in 11 trials with 1,883 patients. A comparison of current series with literature review at standard dose follows (table 1).

Conclusion: Compared with previously published data, CAPE-L appeared more tolerable with comparable clinical efficacy as package insert doses.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-03.
Abstract P1-12-08: Quality of Life in Patients with Locally Advanced or Metastatic Breast Cancer Previously Treated with Anthracyclines and Taxanes who Received Eribulin Mesylate or Capecitabine in a Phase III, Open-label, Randomized Study
Authors: Cortes Javier , Awada Ahmad , Twelves Christopher , Yelle Louise , Wanders Jantien , Olivo Martin S , Simons W Robert , Dutcus Corina E , Kaufman Peter A
Published: August 2014

Withdrawn by Author.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-08.
Abstract P1-13-04: Optimal duration of adjuvant chemotherapy for high risk node negative breast cancer patients: 6-year results of the prospective randomized phase III trial PACS 05.
Authors: Kerbrat P , Coudert B , Asselain B , Levy C , Lortholary A , Marre A , Delva R , Rios M , Viens P , Brain E , Serin D , Edel M , Mauriac L , Campone M , Mouret-Reynier M-A , Bachelot T , Foucher-Goudier M-J , Roca L , Martin A-L , Roche H
Published: August 2014

BACKGROUND: In 2000, the NIH Consensus meeting concluded that 4 to 6 cycles of adjuvant chemotherapy appeared to provide an optimal benefit; So, we underwent a prospective randomized trial comparing 4 and 6 cycles of FEC 100 (JCO 2005; 23: 2686–2693) for high risk node negative breast cancer patients.

METHODS: This study enrolled 18–65 y women with operable breast cancer, without axillary lymph node involvement, or presence of isolated tumor cells, with size superior to 1 cm and another poor prognostic factor: T > 2 cm, HR –, SBR grade II or III, age < 35 y.

After adequate breast surgery and axillary lymph node dissection or sentinel node technique, they were randomized between arm A, 6 cycles of FEC 100, and arm B, 4 cycles, every three weeks. The local regional treatment was completed following usual recommendations. All HR+ patients received hormonal therapy for 5 years. After August 2005, patients with HER2+ tumors were excluded from this study.

The primary end point was PFS at 5 years. This study was powered to detect a 6% difference in favour of 6 cycles.

Between August 2002 and September 2006, 1516 patients were randomized; 1515 are analysed in ITT. Three patients in the B group did not receive any chemotherapy. There is no significant difference between the two arms for tumor and patient characteristics.

RESULTS At a median follow-up of 73 months we observed regarding PFS a low event rate, 197 for the entire population (13%) 91 in arm A median PFS, vs. 106 in arm B median PFS, without any difference between the two groups for DFS, DDFS, local relapse, overall survival. There was no unexpected toxicity. In the arm A we observed more grade III and IV neutropenia, without congestive heart failure.

CONCLUSION At a follow-up of 73 months, we observed a low relapse rate, with no significant difference between the two arms. Duration of FEC100 does not induce different outcomes in this population. Question of length of adjuvant treatment is still open with and without taxanes.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-04.
Abstract P1-13-13: First planned efficacy analysis of the NNBC 3-Europe trial: Addition of docetaxel to anthracycline containing adjuvant chemotherapy in high risk node-negative breast cancer patients.
Authors: Thomssen C , Kantelhardt EJ , Meisner C , Vetter M , Schmidt M , Martin P-M , Veyret C , Augustin D , Hanf V , Paepke D , Meinerz W , Hoffmann G , Wiest W , Sweep FCGJ , Schmitt M , Jaenicke F , von Minckwitz G , Harbeck N ,   the NNBC 3-Europe Study Group
Published: August 2014

Background: Risk assessment in node-negative (N0) breast cancer patients (pts) is routinely performed by established clinico-pathological algorithms (CP) (Schmidt et al. Ann Oncol 2009). ASCO guidelines also recommend invasion markers uPA/PAI-1 (UP; Harris et al. JCO 2007). The prospective randomized multicenter NNBC 3-Europe trial had two questions: 1) Does UP compared to the CP algorithm improve identification of low-risk node-negative breast cancer patients? 2) Does addition of taxanes to adjuvant chemotherapy improve DFS probability in high-risk node-negative breast cancer? Data are mature to report on the second question only.

Methods: Between 2002 and 2009, 4,147 node-negative breast cancer pts were recruited. Risk assessment was performed by CP (43 %) or by UP (57 %). High-risk pts were randomized to receive FE100C*3-Doc*3 (FEC-D) versus FE100C*6 (FEC) as adjuvant chemotherapy. Primary endpoint was disease-free survival probability (DFS). It was planned to accrue 2,572 pts allowing detection of 4% reduction in recurrence probability at 5 years with a power of 80 % at a level of α=0.05 (LogRank) after a minimum observation time of 2.5 years for every recruited patient.

Results: In the intent-to-treat population (ITT, n=2,541), 1,286 high-risk pts received FEC-D, and 1,255 received FEC. In July 2012, 90.8 % of patients had reached the minimum observation time – median follow-up was 43.8, and 44.4 months. Main patients' characteristics were distributed similarly between the two chemotherapy arms: median age was 53 yrs, 37.4 % of pts were premenopausal, median tumor size was 1.90 cm, grade 3 was seen in 53.8 %, hormone receptor status was negative in 30.1 % and HER2 was overexpressed in 20.0 %. Mastectomy was performed in 11 %. All planned courses of FEC-D were given in 84.4 %, of FEC in 91.4 % (p < 0.0001). DFS after 2.5 yrs was for FEC-D 97.5 % (+/− 0.45 %) and for FEC 97.3 % (+/− 0.47 %). Overall-survival probability (OS) after 2.5 yrs was 99.0 % (+/− 0.29 %) for FEC-D and 99.5 % (+/− 0.20 %) for FEC. The survival differences between the two arms were not statistically significant. Per-protocol analysis did not reveal any additional results.

Conclusions: Use of taxanes does not further reduce the rate of early recurrences and led to significantly more treatment discontinuation. Today, with adequate adjuvant chemotherapy even high-risk node-negative breast cancer patients have an excellent prognosis.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-13.
Abstract P1-14-04: Long- term outcome after neoadjuvant radiochemotherapy in locally advanced non-inflammatory breast cancer and predictive factors for a pathologic complete remission; results of a multi-variate analysis
Authors: Matuschek C , Boelke E , Roth S , Bojar H , Audretsch W , Janni JW , Nestle-Kraemling C , Sauer R , Speer V , Budach W
Published: August 2014

Background: An earlier published series of neoadjuvant radio-chemotherapy (NRT-CHX) in locally advanced non-inflammatory breast cancer (LABC) has now been updated with a follow up of more than 15 years. Long- term outcome data and predictive factors for pathologic complete response (PCR) were analyzed.

Patients and Methods: 315 LABC patients (cT1-cT4/cN0-N1) were treated during 1991–1998 with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or – in case of breast conservation – an 10-Gy interstitial boost with 192Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX and the time interval between end of RT and surgery were examined in multivariate terms with as endpoint pCR and overall survival.

Results: The total PCR rate after neoadjuvant RT-CHX reached 29.2 % with LABC breast conservation becoming possible in 50.8%. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1,17 [95% CI 1,05-1,31], p < 0,01). However, in large tumors (T3-T4) a significantly reduced pCR rate (HR 0.89 [95% CI 0.80 to 0.99], p = 0.03) could be obtained. Importantly, a pCR was the strongest prognostic factor for long term survival (HR 0.28 [95% CI 0.19–0.56], p < 0.001).

Conclusions: A PCR identifies patients with a significant better prognosis for long-term survival. However, a long time interval to surgery (> 2 months) increases the probability of a pCR after NRT-CHX.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-04.
Abstract P1-14-05: Phase I/II Trial of primary chemotherapy with non-pegylated liposomal doxorubicin, paclitaxel and lapatinib in patients with HER2-positive, early stage breast cancer
Authors: Aktas B , Kümmel S , Krocker J , Elling D , Lantzsch T , Bischoff J , Fersis N , Böhme M , Belau AK , Lampe D , Schmid P
Published: August 2014

Background: Several studies showed that pathologic complete response (pCR) is a surrogate for disease free survival (DFS) and overall survival (OS). Combinations of trastuzumab and anthracyclines in HER2-positive breast cancer are highly active but associated with a high incidence of cardiotoxicity. The risk of cardiac damage can be significantly reduced through liposomal encapsulation of anthracyclines. This phase I/II study was initiated to evaluate the combination of non-pegylated liposomal doxorubicin (NPLD), paclitaxel and lapatinib as primary treatment for patients with early stage, HER2-positive primary breast cancer.

Patients and Methods: Patients with newly diagnosed HER2-positive (IHC 3+ or FISH+) early stage (T1c N1-2 or T2 N0-2) breast cancer were treated with NPLD (60mg/m2; day 1), paclitaxel (175mg/m2, day 1) and lapatinib (750–1500 mg orally daily) in 3-week intervals for up to 6 cycles. The primary endpoints were dose-limiting toxicities (DLT) and pathological complete response (pCR). Secondary endpoints include safety, incidence of cardiac events, and clinical response. Exploratory endpoints include molecular markers for sensitivity or resistance to chemotherapy and/or lapatinib evaluated.

Results: A total of 84 patients have been included. No dose-limiting toxicity were observed and the maximum tolerated doses were NPLD 60mg/m2, paclitaxel 175mg/m2 and lapatinib 1500mg. Recommended phase 2 doses (P2D) were NPLD 60mg/m2, paclitaxel 175mg/m2 and lapatinib 1250mg. The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents. No cardiac event has been observed to date. Preliminary efficacy data confirm a pCR breast rate of 41.7% and pCR rate in breast and lymph nodes of 37.5%, in 32 evaluable patients treated at ≥P2D.

Conclusions: The combination of NPLD, paclitaxel and lapatinib is well tolerated and has high antitumor activity in patients with HER2-positive primary breast cancer. Updated results of all 84 patients will be presented.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-05.
Abstract P1-14-10: Final results of neoadjuvant trial of bevacizumab (B) and trastuzumab (T) in combination with weekly paclitaxel (P) as neoadjuvant treatment in HER2-positive breast cancer: A phase II trial (AVANTHER)
Authors: Fernandez M , Calvo I , Martinez N , Herrero M , Quijano Y , Duran H , Garcia-Aranda M , Suarez A , Lopez-Rios F , Perez D , Perea S , Hidalgo M , Garcia-Estevez L
Published: August 2014

Background: B in combination with T has shown meaningful activity in patients (pts) with metastatic HER2-positive breast cancer. Pathological complete response (pCR) was defined as the absence of invasive disease at the time of histological study and there is a relationship between pCR and disease-free survival (DFS) and overall survival (OS). The complete pathological response rate is between 9 to 34% of patients receiving primary treatment prior to surgery with chemotherapy and when the Herceptin was administrated, a pCR of 39% was reached.

AVANTHER is a Phase II trial of preoperative systemic therapy combining B with T and P in a weekly regimen in HER2 positive breast cancer to assess safety and efficacy of the combination.

Methods: Pts with centrally-confirmed HER2− positive (IHC 3+ or FISH positive) breast cancer (stage II or III including locally advanced) received neoadjuvant chemotherapy (NC) with weekly P (80mg/m2/week) for 12 weeks in combination with weekly T (4mg/kg loading dose and 2 mg/kg maintenance) and B (15mg/kg every 3 weeks) for 4 cycles. After surgery all pts received T (1 year) and liposomal doxorubicin plus cyclophosphamide every 3 weeks (4 cycles); primary endpoint was rate of pathological complete response (pCR) in breast and axilla. For all patients, a tissue sample at baseline as well as at surgery was collected for biomarker analyses.

Results: A total of 44 pts have been enrolled. Median tumor size: 3.9 cm. Nine (21%) pts had stage IIA; 19 (45%) stage IIB; 10 (24%) stage IIIA and 4 (10%) stage IIIB. Twenty-nine (69%) pts had estrogen positive receptors.

Data from surgery of 42 patients from a total of 44 patients enrolled were presented in this abstract, but the final results will be present in the symposium. pCR was achieved in 18 (42.9%) pts. Safety and tolerability were good, with rare adverse events of grade 3 [1 (2.4%) episode of severe hypertension, 1 (2,4%) mucosal inflammation].

We presented the results of relationship between magnetic resonance imaging (MRI) and pCR that is one of the secondary objectives of the study.

100% of the patients without pathologic response had stable disease at resonance imaging. Of all patients who had pCR only 55.6% had complete radiological response.

Conclusions: These data show that the combination of P with T and B without an anthracycline for 12 weeks is very effective as NC in HER2 positive breast cancer pts with a high rate of pCR and minimal side effects.

And the MRI is useful for identifying the persistence of residual disease however it only predicts half of the complete pathological responses

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-10.
Abstract P1-14-16: Young age: predicts poor response rate after neoadjuvant chemotherapy in endocrine-responsive breast cancer
Authors: Kim MK , Noh D-Y , Han W , Moon H-G , Ahn S-K , Kim JS , Kim T , Kim JY , Lee JW
Published: August 2014

Background: Breast cancer rarely occurs in very young women(age<35years), its diagnosis and management could sometimes be difficult. Especially, the patients with positive hormone receptors have significantly lower overall and disease-free survival rates in very young age group than in the older age group. In the previous study, adjuvant tamoxifen therapy might provide less survival benefit when added to chemotherapy in very young breast cancer patients. This study was to compare the response to neoadjuvant chemotherapy for HR-positive breast cancer patients according to the age.

Patients and Methods: A total of 551 consecutive patients were evaluated, received preoperative chemotherapy and referred to surgery at the Seoul National University Hospital from January 2001 to December 2010. The clinicopathologic factors and the response to neoadjuvant chemotherapy between the very young age group and the older age group were retrospectively compared. A pCR was defined as the absence of residual invasive carcinoma in the breast.

Results: Among the 551 patients who received neoadjuvant chemotherapy, 297 patients revealed HR-positive. The median age of all patients was 42 (range, 24∼67)years and very young age group accounted for 17.2%(51/297). Of 297 patients, 262 (88.2%) received taxane-containing regimen pre-operatively, and there's no difference of chemotherapeutic regimen between two age groups. There were no differences noted between two age groups about clinicopathologic characteristics. The univariate and multivariate analysis of variables related to ORR(CR+PR vs SD+PD) to neoadjuvant chemotherapy showed that very young age at diagnosis was independent predictive factor for poor neoadjuvant chemotherapeutic response.(p = 0.043, OR = 0.528) And this tendency was observed more significantly in age under 30.(p = 0.001, OR = 0.147) Only thirteen patients(4.4%) achieved pCR, which is relatively lower rate, reflective poor chemotherapeutic response in HR-positive group, and there was no relations between pCR rate and the two age groups(p = 0.861) in this study. Taxane-containing regimen(p = 0.004) and Ki67 level(p = 0.005) were related to pCR statistically significantly. Breast conservation rate is not significantly different between two age groups.(age<35: age>35= 51.2% vs 41.3%, p = 0.150)

Conclusions: The very young age group showed lower ORR(CR+PR) to neoadjuvant chemotherapy, although there was no significant difference in pCR rate between the two age groups in HR-positive breast cancer patients. We might have to consider and revalue the chemotherapeutic role as neoadjuvant therapy in very young age, HR-positive group, since they had lower survival rate than others.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-16.
Abstract P1-14-20: Meta-analysis Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC)
Authors: Cortazar Patricia , Zhang Lijun , Untch Michael , Mehta Keyur , Costantino Joseph , Wolmark Norman , Bonnefoi Hervé , Cameron David , Gianni Luca , Valagussa Pinuccia , Zujewski Jo Anne , Justice Robert , Loibl Sibylle , Wickerham Lawrence , Bogaerts Jan , Baselga Jose , Perou Charles , Blumenthal Gideon , Blohmer Jens , Mamounas Eleftherios , Bergh Jonas , Semiglazov Vladimir , Prowell Tatiana , Eidtmann Holger , Paik Soonmyung , Piccart Martine , Sridhara Rajeshwari , Fasching Peter , Swain Sandra M , Slaets Leen , Tang Shenghui , Gerber Bernd , Geyer Charles , Pazdur Richard , Ditsch Nina , Rastogi Priya , Eiermann Wolfgang , von Mincwitz Gunter
Published: August 2014

Withdrawn by Author

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-20.
Abstract P1-15-03: Comparison of efficacy of primary prophylaxis with pegfilgrastim, filgrastrim and a biosimilar filgrastim in TAC regimen (docetaxel, doxorubicin and cyclophosphamide)
Authors: Brito M , Esteves S , Andre R , Isidoro M , Moreira A
Published: August 2014

Background: Febrile neutropenia (FN) is a major toxicity of myelosupressive chemotherapy. Primary prophylactic use of granulocyte colony stimulating factors (G-CSF) is recommended in high risk FN regimens.

The comparison of pegfilgrastim (Peg) and filgrastim (Fil) FN prophylactic effectiveness is still an issue of debate. Very recently Nivestim (Niv), a new biosimilar filgrastim, has also become commercially available.

We aimed to compare the efficacy of the 3 mentioned types of G-CSF in the primary prophylaxis of FN.

Methods: Single-center, retrospective study to evaluate the incidence of FN in women with breast cancer treated with adjuvant or neo-adjuvant TAC (FN risk ≥20%). Patients (Pt) were divided in 3 consecutive cohorts according to G-CSF primary prophylaxis (Fil, Peg and Niv) FN was defined as axillary temperature ≥38,3 °C and absolute neutrophil count < 500/ul.

Results: We included a total of 421 women (median age 51 y, 25–76) with Stage II (56%) and Stage III (44%) breast cancer. Age and stage distribution were similar in the 3 cohorts.

A single dose of Peg was administered in all 767 cycles (cy). The standard dose of Fil and Niv was 7 daily injections, only in in 13% Fil pt and 10% Niv pt < 7 administrations were done.

The incidence of FN per patient and per cycle is presented in Table 1. In all cohorts, approximately half of NF episodes occurred in the 1st cycle (48% Fil, 59% Peg, 42% Niv).

Conclusions: No differences in terms of efficacy existed between Biosimilar Niv and original biological reference Fil.

Seven daily injections of Fil and Niv seem equivalent to single dose Peg.

Besides efficacy, questions like cost-effectiveness and convenience of administration should be taken into account when approaching this topic.

Our data showed a predominance of events in the 1st cycle (regardless of the type of G-CSF). This has been consistently described in the literature and may support the necessity to recommend other NF preventive measures in this cycle.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-03.
Abstract P1-15-04: The relationship of relative dose intensity and supportive care to febrile neutropenia rates in patients with early stage breast cancer receiving chemotherapy: a prospective cohort study of chemotherapy-associated toxicity
Authors: Culakova E , Poniewierski MS , Wogu AF , Kuderer NM , Crawford J , Dale DC , Lyman GH
Published: August 2014

Background: Febrile neutropenia (FN) represents a major dose-limiting toxicity of cancer chemotherapy resulting in considerable morbidity, mortality, and cost. Patients have the highest risk of the initial neutropenic event in cycle 1 when most patients receive full dose chemotherapy. This study evaluates time course of neutropenic events in patients receiving chemotherapy for early-stage breast cancer (ESBC) and supportive care interventions that modify FN risk in ESBC patients treated in actual oncology practice.

Methods: A prospective cohort study of adult cancer patients with solid tumors or lymphoma starting a chemotherapy regimen was conducted at 115 U.S. sites. Toxicities associated with chemotherapy were recorded in up to 4 cycles including severe neutropenia (SN), FN, and infection. Documented clinical interventions included reductions in chemotherapy relative dose intensity (RDI), the use of colony-stimulating factors (CSFs), and antibiotics.

Results: A total of 1202 ESBC patients starting chemotherapy were analyzed, of which 1154, 1099, and 896 reached the midcycle of cycles 2, 3, and 4, respectively. While the majority of neutropenic and infection events occurred in cycle 1, decreasing rates of FN and infection in later cycles correlated with increasing reductions in dose intensity and increased use of CSFs and antibiotics.

The overall risk of FN in all patients combined was 16.3 %. It reached 21.1% for patients who started with planned RDI≥85% and without primary CSF prophylaxis. There was no significant difference in FN rates by menopausal status or hormone receptors.

Conclusions: While the risk of neutropenic complications is highest during the first cycle of chemotherapy, reductions in neutropenic events during subsequent cycles are associated with reduced chemotherapy dose intensity or increased use of supportive care measures. Nevertheless, the cumulative risk of neutropenic events remains high in ESBC patients receiving full dose chemotherapy without prophylactic measures overall and across menopausal and hormone receptor subgroups.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-04.
Abstract P2-01-12: Circulating tumor cells and Epithelial Mesenchymal Transition in primary breast cancer patients.
Authors: Mego M , Karaba M , Minarik G , Benca J , Sedlackova T , Manasova D , Sieberova G , Gronesova P , Pechan J , Mardiak J , Reuben JM
Published: August 2014

Background: Circulating tumor cells (CTCs) are prognostic in breast cancer (BC) patients. CTCs represent a heterogeneous population of cells with different phenotypes and biological value. Epithelial-mesenchymal transition (EMT) gives rise to cells with stem cell-like properties with increased chemotherapy resistance and may be responsible for undetection of CTC by conventional methods in a fraction of patients with early or advanced breast cancer. The aim of this study was to characterize CTCs based on the expression of epithelial and mesenchymal markers in non-metastatic breast cancer patients before surgery.

Methods: This prospective ongoing translational study consists of 36 patients with non-metastatic breast cancer. CTCs were detected before surgery, before 1st cycle and before 2nd cycle of adjuvant therapy. Herein, we present preliminary data related to CTCs detection before surgery. Isolated peripheral blood mononuclear cells (PBMC) were depleted of cells of hematopoietic origin (CD45+) using RossetteSep kit (StemCell Technologies) negative selection with anti-CD45 antibody. RNA extracted from CD45-depleted (CD45−) PBMC was interrogated for expression of EMT-inducing transcription factors (TWIST1, SNAIL1, SLUG, FOXC2) and epithelial (CK19, EpCAM) gene transcripts by quantitative reverse transcription-PCR. Expressions of gene transcripts in CD45- PBMC from patients were compared to those of CD45- PBMC of 30 healthy donors (HD).

Results: Median age was 62 year (range: 40–80 years). TWIST1, SNAIL1, SLUG, FOXC2, CK19 and EpCAM were overexpressed in CD45- PBMC in 2.8%, 2.8%, 11.1%, 13.9%, 19.4% and 2.8% respectively. Totally, CTCs were detected in 36.2% of patients. CTCs with only epithelial markers were present in peripheral blood of 5.6% patients; CTC with EMT phenotype were present in 13.9% of patients, while in 16.7% of patients CTCs exhibited both epithelial and mesenchymal markers. Overexpression of different EMT-related transcription factors in peripheral blood samples were mutually exclusive. There was no association between the presence of CTCs and analyzed clinico-pathological variables.

Conclusions: CTCs with EMT phenotypes are more prevalent compared to CTCs with epithelial phenotype in early breast cancer patients before surgery, and EMT genes may be involved in the dissemination of CTCs. These data support the concept of CTCs heterogeneity in breast cancer patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-12.
Abstract P2-04-04: Prolactin cooperates with loss of p53 to promote mammary tumorigenesis.
Authors: O'Leary KA , Sullivan R , Rugowski DE , Schuler LA
Published: August 2014

Prolactin (PRL) is critical for mammary development and lactation. Epidemiological studies also support a role for PRL in breast cancer. In order to study the contributions of PRL to tumor development and progression, we developed a transgenic mouse model that expresses PRL in the mammary epithelial cells (NRL-PRL), mimicking the mammary PRL production in women. Loss of function of the tumor suppressor p53 is a common occurrence in many human cancers including breast tumors. Interactions between PRL and p53 were examined by crossing the NRL-PRL mouse to p53 knockout mice which were made congenic on the FVB/N background. To circumvent the problem that p53−/− mice are prone to multiple nonmammary tumors, mammary cells from 10–12 week old wild-type, NRL-PRL, p53−/−, and NRL-PRL/ p53−/− were transplanted to wild type mammary glands. Histological analysis of the donor glands showed that NRL-PRL glands displayed marked epithelial proliferation and focally dilated ducts, whereas p53−/− glands exhibited irregular ductal epithelium with increased stromal density compared to wild type mice. In contrast, glands of donor PRL/ p53−/− females showed widespread epithelial hyperplasias and highly irregular ductal epithelium often surrounded by dense stroma. By one year of age, no tumors had developed from either wild-type or NRL-PRL transplanted epithelium. However, recipients of either p53−/− or NRL-PRL/ p53−/− mammary epithelium developed histologically similar anaplastic carcinomas. The presence of transgenic PRL decreased tumor latency (205 vs 244 days) and significantly increased tumor cell proliferation. In addition, these carcinomas appeared to be more aggressive: 5/16 (32%) of the NRL-PRL/ p53−/− tumors invaded into the peritoneal cavity, compared to 0/10 p53−/− tumors. Expression of matrix metalloproteinase 9 (MMP-9), but not MMP-2, was found to be significantly higher in the NRL-PRL/ p53−/−, compared to p53−/− tumors. MMP-9 is regulated by the transcription factor, AP-1, and PRL can signal through AP-1. NRL-PRL/ p53−/− tumors displayed significantly increased expression of the AP-1 family members, c-Jun and FosL, but not JunD or c-Fos compared to tumors from p53−/− mice. In addition, levels of c-Jun and FosL proteins increased in a similar pattern. In summary, interactions between PRL and loss of p53 promote breast cancer by increasing proliferation and invasiveness, potentially via AP-1 target genes. Supported by CDMRP BC053412.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-04-04.
Abstract P2-05-03: Mouse double minute 2 nuclear expression as a prognostic marker in patients with breast cancer
Authors: Park HS , Park S , Koo JS , Cho JH , Park JM , Kim S-I , Park B-W
Published: August 2014

BACKGROUND: Mouse double minute 2 (Mdm2) is a negative regulator of tumor suppressor, p53, thus Mdm2 expression may play a role in cancer development and prognosis, however, the definite role of Mdm2 in breast cancer is unclear. The aim of the study is to evaluate the correlation between Mdm2 expression and prognosis of breast cancer.

METHODS: Mdm2 expression was determined from immunohistochemistry of tissue microarrays of 865 patients with breast cancer who underwent surgery. Clinicopathologic characteristics and survival data were analyzed using a univariate and multivariate analysis. Mdm2 expression was categorized into 3 groups: negative; no Mdm2 expression in nucleus and cytoplasm, cytoplasm-positive; cytoplasmic expression of Mdm2, nucleus-positive; nuclear with or without cytoplastimc expression of Mdm2.

RESULTS: Negative, cytoplasm-positive, and nucleus-positive groups were observed in 59.2%, 10.9%, and 29.9% of patients, respectively. Nucleus-positive group was associated with young age, high grade, negativity of estrogen and progesterone receptor, HER2 positivity, and high Ki-67 index. With median 86.0 follow-up months, nucleus-positive group showed poorer disease-free survival and overall survival than negative and cytoplasm-positive groups. In multivariate analysis, cytoplsmic expression of Mdm2 was not significantly associated with survival, whereas nuclear expression of Mdm2 was related to poor prognosis. (HR, 1.44; 95% CI, 1.041–1.993 for DFS; HR, 1.546; 95% CI, 1.060–2.255 for OS)

CONCLUSIONS: Nuclear expression of Mdm2 was an independent prognostic factor in patients with breast cancer. Patterns of Mdm2 expression in tumor cell should be rendered in the evaluation of Mdm2 in breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-03.
Abstract P2-05-08: Determination of HER2 amplification by dual-color in situ hybridization before and after neoadjuvant chemotherapy
Authors: Niikura N , Kumaki N , Iwamoto T , Tsuda B , Okamura T , Yuki S , Suzuki Y , Tokuda Y
Published: August 2014

Background: HER2-targeted therapies such as trastuzumab neoadjuvant chemotherapy for patients with HER2-positive breast cancer can increase pathological complete response (pCR) better than non-HER2-targeted therapies. Previous studies have suggested that trastuzumab may convert HER2-positive (HER+) primary breast tumors to HER2 negative (HER−) after neoadjuvant chemotherapy. We compared the HER2 status in breast cancer patients before and after neoadjuvant treatment by using dual-color in situ hybridization (DISH).

Methods: We retrospectively identified 46 patients from the Breast Cancer database at Tokai University Hospital, in whom HER2-positive primary breast cancer was diagnosed between 2000 and 2010, and who were treated with neoadjuvant chemotherapy or endocrine therapy with or without trastuzumab. Surgical specimens from patients achieving less than pCR were assessed to determine if there was enough residual tissue to evaluate the post-treatment HER2 status by DISH. HER2 status was defined as positive if DISH demonstrated a gene copy ratio of HER2:CEP17 >2.0. Paraffin tissue sections (4-μm thick) were mounted on glass slides (New Sliane III, Catalog No. 5126–25; MUTO PURE CHEMICALS, CO. LTD., Tokyo, Japan) and stained using the newly developed, fully automated HER2 Dual ISH assay on a BenchMark® XT slide stainer according to the recommended procedure (Ventana Medical Systems Inc., Tucson, AZ). Thereafter, the stained slides were rinsed with tap water containing neutral detergent and then rinsed again with distilled water. The slides were dried at room temperature for at least 60 min and cover-slipped with cover grass for SGC (MUTO PURE CHEMICALS). HER2 Dual ISH and H&E images were obtained using an Olympus BX51 microscope.

Results: A pCR was achieved in 9 of the 46 patients (19.6%). Specimens from core needle biopsy were not sufficient to assess the pretreatment HER2 status in 3 patients. In 9 patients, the post-treatment HER2 status could not be assessed because residual tumors were DCIS only in 4 patients and there were less than 20 invasive cells in 5 patients. Residual tumor was sufficient to assess the post-treatment HER2 status in 25 patients. In pretreatment specimens, of the 25 patients identified as HER2 + by immunohistochemical analysis, 3 patients were identified as HER2− by DISH. No post-treatment specimens were found to be HER2− by DISH among the tumors identified as HER2+ by DISH at pretreatment. Among the 3 pretreatment tumors identified as HER2− by DISH, 1 tumor was found to be HER2+ by DISH at post-treatment, and 2 showed a stable HER2 status.

Conclusion: DISH revealed a stable HER2 status in pretreatment breast tumors and in residual tumors. However, we found a discrepancy in the HER2 status between the immunohistochemical analysis and DISH.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-08.
Abstract P2-06-03: Specific Transcriptional Response of Four Blockers of Estrogen Receptors on Estrogen-Modulated Genes in ZR-75-1 Breast Cancer Xenografts
Authors: Calvo E , Luu-The V , Martel C , Labrie F
Published: August 2014

Introduction: Acolbifene (ACOL) is a novel compound completely free of estrogen-like activity in both the human and rat mammary gland and uterus. In previous studies, it was observed that ACOL could have a cytotoxic or tumoricidal rather only tumorostatic activity, with a lack of development of tumor resistance. The objective of the present study was to obtain information on the molecular basis of the tumoricidal properties of acolbifene, as well as on the identity of the genes potentially implicated in the resistance to tamoxifen (TAM). The specificity of action of ACOL was compared to the pure antiestrogen fulvestrant (FUL) as well as to tamoxifen (TAM) and raloxifene (RAL).

Methods: The gene expression profile of the ZR-75-1 breast cancer xenografts was studied following treatment with ACOL, RAL, TAM and FUL. Ovariectomized female nude mice (10/group) bearing human ZR-75-1 breast cancer xenografts were supplemented with estrone (E1) (subcutaneous silastic implants) and were injected daily with the vehicle alone or 50 μg of ACOL, RAL, TAM or FUL for 6 months. Mice were killed 24h after the last injection and ZR-75-1 tumors were collected and processed for RNA extraction and microarray analyses (Affymetrix GeneChip U133 Plus 2.0).

Results: Long-term exposure of ZR-75-1 xenografts to E1 causes a massive modulation of E1-responsive genes. When the antiestrogens were administered simultaneously with E1, some compound-specific prevention of the effect of E1 was observed. Globally, the efficacy of the compounds was ACOL>FUL or RAL>TAM. ACOL significantly prevented the effect of E1 on 195 responsive genes. Among these, the most enriched gene ontological group in Molecular Function was Receptor Activity, including ER, insulin, retinoid and thrombospondin receptor activity. One of the transcriptional repressors of the estrogen signaling pathway, the NKX31, was down-regulated by E1 and completely blocked by ACOL (fold-change −1.64 and 2.54, respectively). The most enriched biological processes were associated with mammary gland development, positive regulation of glucose metabolic processes and blood vessel morphogenesis. Between the genes implicated in cell death/apoptosis of breast cancer cells, the changes of expression of 57, 51, 48 and 31 genes were significantly neutralized by ACOL, RAL, FUL and TAM, respectively. Sixteen genes implicated in tumor resistance to TAM were significantly blocked by ACOL, including DEGS1, a gene implicated in the inhibition of EGF receptor biosynthesis. The other 15 genes in the group were up-regulated by E1, changes which were significantly blocked by ACOL.

Conclusion: The present data offer a possible explanation for the potent tumoricidal action of acolbifene in human breast cancer xenografts, thus offering a new paradigm in the hormonal therapy of breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-06-03.