bluuebunny/crossref_metadata_2025 huggingface dataset:
P3-07-21: Sentinel Lymph Node Metastasis Are More Likely To Develop in Triple Positive Breast Cancer Patients without Compromising Disease Free Survival.
Authors: Rubio IT , Espinosa-Bravo M , Cebrecos I , Sao A , Peg V , Di Cosimo S , Cortes J , Xercavins J
Published: June 2012

Background. Lymph node metastasis are the most significant prognostic factor for breast cancer (BC) patients and the use of sentinel lymph node biopsy (SLN) has generated an increased detection of positive nodes. In the last years, molecular subtypes have provided additional information on local recurrence and survival in BC patients. The objective of this study is to evaluate the correlation between axillary SLN metastasis and molecular subtypes and whether this may have prognostic implications.

Methods. A total of 497 patients with clinically node negative T1-T3 breast cancer underwent SLN biopsy from 2005 to 2009. Patients were divided in two groups depending on the timing of SLN biopsy. Patients were classified according to ER/PR/Her2 status as (ER/PR/HER2 + (TP), ER/PR/HER2 - (TN), ER/PR/+ HER2 - and ER/PR -HER2 +). For SLN metastasis the following variables were tested in univariable and multivariate models: age, tumor grade, tumor type, and the combined hormone receptors and HER2.

Results: The SLN was positive in the surgery first group in 127 of 429 patients (29.6 %) while in 27 patients (34.7%) in the neoadjuvant group (p = 0.08). Forty patients (8.1%) were classified as TP, 25 (5.1%) as ER/PR - HER2 +, 364 (73.2%) as ER/PR+ HER2 - and 68 (13.6%) as TN. Triple positive BC patients were more likely to have axillary SLN metastasis compared to other molecular subtypes (p < 0.006). Multivariate logistic regression revealed age (≤ 50 years) and TP tumors to be independent predictors of SLN metastasis. Odds ratio (OR) for TP vs other molecular subtypes was 3.646 (IC 95% 1.566−8.488). OR for age ≤ 50 years was 2.353 (IC 95% 1.554−3.559). Disease free survival in TP patients tended to be longer compared to ER/PR - Her2 + and TN patients.

Conclusions. Her 2 overexpression favours SLN metastasis in ER/PR positive tumors over other ER/PR status. Even with increased SLN metastasis, TP breast cancer patients do better than TN and ER/PR -/Her2 positive patients. Molecular subtype classification may holds more potential value in the decision-making process in patients with BC than the currently staging system.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-21.
P3-07-24: Accuracy and Cost Effectiveness of Frozen Section Examination of the Sentinel Lymph Node (SLN) in Ductal Carcinoma In Situ (DCIS) of Breast.
Authors: Ballehaninna UK , Santoro E , Schaefer SS , Blackwood MM , Chamberlain RS
Published: June 2012

Background: SLN biopsy (SLNB) can avoid reoperation for axillary staging in DCIS patients upstaged to invasive breast cancer (IBC) following resection. Intraoperative frozen section (IFS) examination of the SLN is a widely accepted tool for IBC patients in order to select candidates for axillary lymph node dissection (ALND), and avoid reoperation. Until now, utility of IFS in DCIS patients has not been addressed.

Methods: Data from DCIS patients undergoing resection with SLNB (2000-11) was analyzed to determine the utility and cost of IFS exam and its impact on axillary management. A binomial regression analysis was performed to assess factors predictive of IFS positivity and SLN metastases (SLNM).

Results: 401 patients (core biopsy, N=276, or excisional biopsy, N=125) underwent partial (N=84) or total mastectomy (N=317) with SLNB. 77 patients (19.2%) were upstaged to IBC. SLNM were identified in 24 patients (5.9%). Immunohistochemistry (IHC) positive individual tumor cells (ITCs) was the most common pattern of SLNM (N=12, 50%), SLN micrometastasis (SLNmi) was identified in 9 patients (37.5%) and macrometastases in 3 patients (12.5%). IFS exam was positive in only 5 patients (1.2%) with a sensitivity and specificity of 20.8% and 100%. IFS was negative in 396 patients (98.7%) yielding a false negative rate (FNR) of 79.2%.

IFS costs $300,480 in DCIS patients of which only $2,970 was applicable to IFS positive patients (N=5). 11 of 24 patients with SLNM underwent ALND, revealing only 1 patient with further metastasis. Presence of IBC or DCIS with micro-invasion, multi-focal/multi-centricity, and advanced tumor stage were associated with SLNM (p<0.05), however no clinico-pathologic variables were predictive of IFS positivity.

Conclusions: Most common patterns of SLNM in DCIS (ITCs/SLNmi) were identified only on routine pathologic assessment. Utility of IFS examination in DCIS patients is limited by poor sensitivity, high FNR and increased costs. Higher axillary nodal metastases are rare and prognostic significance of SLNmi/ITCs in DCIS is unproven. IFS examination of SLN in DCIS can be safely omitted and ALND should be performed only for SLN macrometastases.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-24.
P3-07-28: One Step Nucleic Acid Amplification (OSNA) for Intraoperative Molecular Detection of Lymph Node Metastases and Micro-Metastases in Breast Cancer.
Authors: Babar MM , Madani R , Jackson P , Irvine T , Layer G , Kissin M
Published: June 2012

Introduction: Ideally, intraoperative sentinel lymph node analysis in breast cancer should be automated, concordant with histopathology and practically applicable. One step nucleic acid amplification (OSNA), a highly sensitive intraoperative assay of cytokeratin 19 mRNA, is used for the detection of sentinel lymph node (SLN) macro- and micro-metastases in breast cancer. Guildford adopted the intraoperative OSNA “live” in December 2008 after undertaking a multicentre evaluation of its accuracy and high concordance with histopathology and here we present our two year data since its introduction.

Methods: Data was collected prospectively from 2008–10. All patients eligible for sentinel node biopsy were offered OSNA and operations were performed by five consultant breast surgeons. On detection of micro-metastasis (+) and positive but inhibited metastases a level 1 axillary nodal clearance (ANC) and for a macro-metastasis (++), a level 3 ANC was performed.

Results: 471 patients had 999 SLN analysed, median age being 61. All except one were females. 72% (n=340) had wide local excision, 26% (n=120) underwent mastectomy and 2% (8) SNB alone. Mean tumour size was 18.3 mms. 80% (n=371) of the cases were IDC and 55% (n=256) had grade II tumour. 34% (n=161/471) had positive SLN who had further ANC. Of these, 48% (n=78/161) had macro-metastases, 37% (n=59/161) had micro-metastases and 15% (n=24/161) had positive but inhibited results. 17% (10/59) of the patients with micrometastases had positive non-SLN (NSLN), four (4/59, 6.8%) had four positive nodes (SLN+NSLN) thus receiving adjuvant radiotherapy. 8% (2/24) of those with positive but inhibited results and 39% (30/78) of those with macro-metastases had positive NSLN.

Conclusion: Over a third of patients had OSNA positive SLN and underwent axillary surgery at the same operation. This technique eliminates the need for a second operation in sentinel lymph node positive patients and avoids the anxious wait for results in all, streamlining the patient's cancer journey. OSNA upstages patients with micro-metastases and long term studies are needed to determine the clinical relevance of molecular micro-metastatic disease.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-28.
P3-10-01: Alternative Dosing Regimens with the EGFr Inhibitors (Gefitinib and Lapatinib) in Mammary Cancer Models: Prevention and Therapeutic Efficacy.
Authors: Lubet RA , Bode AM , Szabo E , Grubbs CJ
Published: June 2012

The EGFR inhibitors are effective in treatment of lung and pancreatic cancers (erlotinib, gefitinib) and Neu overexpressing breast cancer (lapatinib) in humans; as well as preventing multiple cancers in animal models. However, the development of toxicities (Iressa, skin rashes; Lapatinib, diarrhea) limit their potential use in prevention; and perhaps even in an adjuvant setting. We examined whether alternative dosing regimens which might reduce toxicity would still achieve preventive and therapeutic efficacy. Female Sprague-Dawley rats were administered a single IV dose of methylnitrosourea (MNU) at 50 days of age. In a prevention study, MNU treated rats administered Gefitinib daily (10 mg/kg BW/day, 7x/week) or Gefitinib (70 mg/kg BW, 1x/week) beginning 5 days after MNU resulted in 94 and 75% reductions, respectively, in cancer multiplicity. Simultaneous measurements of tumor load (number of tumors x tumor weight) showed that both regimens resulted in greater than a 90% decrease. In the therapeutic study (initiating treatment when animals developed a small palpable cancer), both regimens were again highly effective. A prevention study was also performed with Lapatinib (75 mg/kg BW/day, 7x/week or 525 mg/kg BW, 1x/week). While the daily dose reduced cancer multiplicity 90%, the weekly dose caused a 70% reduction. Finally, we examined the effects of daily or weekly dosing with Iressa (100 mg/kg BW/day, 5x/week or 500 or 250 mg/kg BW, 1x/week) in an ER− mouse model (using MMTV-Neu; p53+/− mice). This study showed that while daily dosing with Iressa decreased tumor multiplicity roughly 80%, weekly dosing at either dose caused roughly a 50% decrease. These data show that even a significant alteration in the dosing of Gefitinib (EGFR 1) or Lapatinib (EGFR 2/1) still resulted in a large reduction in mammary cancers. The important clinical question will be whether this altered dosing will diminish the toxicities associated with these agents. We cannot determine this in animal models since, at the effective doses employed, the typical toxicities observed in humans are not observed. Supported by NCI contract number HHSN261200433001C.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-10-01.
P3-14-01: Panitumumab in Combination with FEC 100 (5-Fluorouracile, Epirubicin, Cyclophosphamide) Followed by Docetaxel (T) in Patients with Operable, Triple Negative Breast Cancer (TNBC): Final Results of a Multicentre Neoadjuvant Pilot Phase II Study.
Authors: Nabholtz J-M , Weber B , Gligorov J , Mouret-Reynier M-A , Tredan O , Vanlemmens L , Petit T , Mayer F , Van Praagh-Doreau I , Dubray-Longeras P , Nayl B , Ferriere J-P , Jouannaud C , Devaud H , Tubiana-Mathieu N , Abrial C , Kwiatkowski F , Planchat E , Chalabi N , Penault-Llorca F , Chollet P
Published: June 2012

Background: Panitumumab is an antibody targeting the epidermal growth factor receptor (EGFR) to which a role has been suggested in TNBC. Consequently, we evaluated the combination of a standard chemotherapy (FEC 100 followed by T) with panitumumab as neoadjuvant therapy of oprable TNBC.

Methods: 60 patients with stage II-IIIA disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 4 cycles of FEC 100 (500/100/500 mg/m2) q.3 weeks followed by 4 cycles of T (100 mg/m2) q.3 weeks, in combination with panitumumab (9 mg/kg) for 8 cycles q.3 weeks. All patients underwent surgery at completion of ST. Complete pathologic response (pCR) was the primary endpoint (Sataloff/J Am Coll Surg 1995; Chevallier: Am J Clin Oncol 1993), with toxicity and biologic ancillary studies as secondary endpoints.

Results: Patients characteristics are as follows: mean age 47 [27-72]; T2: 74%, T3: 26%, (mean tumor size: 40 mm [20-120]); N0: 65%, N1: 28% and N2: 7%; invasive ductal carcinoma: 96%; Scarff-Bloom-Richardson Grade III: 72%, grade II: 28%. The median number of cycles was: FEC 100: 4 [2-4], T: 4 [0-4], Panitumumab: 7 [1-8]. Pathological response showed a pCR according to Sataloff's classification of 57.1% [95% IC: 40.7−73.5] and according to Chevallier's classification of 51.4% [95% IC: 34.8−68.0] with an overall clinical response rate of 60% (29% CR) [95% IC: 43.8−76.2]. Conservative surgery was performed in 79% of cases. Skin toxicity was the main side-effect: Cutaneous toxicity grade IV: 12%, grade III: 26%, grade II: 23%. No ocular complications have been reported. Neutropenia grade IV: 23.7%; febrile neutropenia: 4.2%. Infection: 0%. Hand-foot syndrome grade III: 4%. Ungueal toxicity grade IV: 2.5%, grade II: 25 .5%.

Conclusions: These results suggest that Panitumumab in combination with FEC100 followed by T appears efficacious with acceptable toxicity in the neoadjuvant therapy of operable TNBC.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-01.
P3-14-10: Early Predictive Value of Non-Responder to Docetaxel in Neoadjuvant Chemotherapy in Breast Cancer Using 18F- FDG-PET.
Authors: Hirakata T , Fujisawa T , Yanagita Y , Horikoshi H , Oya N , Akiyoshi T , Kinoshita T , Kuwano H
Published: June 2012

Background; Clinical response is determined after several cycles of chemotherapy by changes in tumor size in imaging procedures including ultrasound, MRI or CT. The aim of this prospective study was to early detect non-responder to docetaxel (DTX) in neoadjuvant chemotherapy using 18F- FDG-PET in patients with breast cancer. Method; 41 patients were eligible for this study. 37 were assessable (4 were not eligible or not evaluable) with Invasive carcinoma (T1:10%, T2: 83%). All 37 patients were treated with 4 cycles of docetaxel (75mg per square meter) followed by 4 cycles of FEC(cyclophosphamide/epirubicin/fluorouracil: 500/75/500 mg per square meter) before surgery. 18F-FDG-PET response rate was evaluated between before and after the first cycle of DTX. 18F-FDG-PET images were analyzed by standardized uptake value, SUVmax. Clinical response is determined by reduction rate in tumor size with MRI (RECIST criteria) between before the first cycle and after the fourth cycle of DTX. Pathological response evaluated by core needle biopsy after the fourth cycle of DTX.

Result; 18F-FDG-PET response rate after the first cycle of DTX showed correlation with tumor size reduction rate with MRI image after the fourth cycle of DTX (r=0.746)(P <.001). 0 out of 8 patients (0%) revealed cPR with MRI changes in SUV decrease less than 18% (p <.001). 8 out of 13 patients (62%) showed cPR (cCR = 0) with MRI in SUV decrease over 19 to 44% (P <.001). 9 out of 16 patients (56%) were cPR, and 7 out of them (44%) showed cCR with MRI in SUV decrease over 45% (P <.001).

Conclusion; Changes of 18F-FDG SUVs in tumors were statistically significantly different between responding and nonresponding (P <.001). SUV decrease less than 18% after the first cycle indicated potential failure to DTX in neoadjuvant chemotherapy.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-10.
P3-14-18: Primary Tumor Response to Neoadjuvant Chemotherapy Is Significantly Associated with Nodal Pathological Complete Response in Breast Cancer Patients with Cytologically Proven Axillary Node Metastasis.
Authors: Hwang H , Park S , Lee JS , Kim S-I , Park B-W
Published: June 2012

Background: Axillary node status is the most significant factor for the prediction of outcome in breast cancer patients whether they received neoadjuvant chemotherapy or not. However, a reliable method to predict nodal response to neoadjuvant chemotherapy is not established yet. The aim of this study was to identify the predictive factors of axillary pathological complete response (pCR) after neoadjuvant chemotherapy in breast cancer patients with cytologically proven axillary lymph node metastases.

Patients and methods: A total of 123 patients with axillary metastases confirmed by ultrasound-guided fine-needle aspiration biopsy were subsequently treated with four cycles of anthracycline (60mg/m2) plus cyclophosphamide (600mg/m2) followed by doxetaxel (75-100mg/m2) between August 2008 and March 2011. After neoadjuvant chemotherapy, all patients underwent a definite breast surgery with complete axillary lymph node dissection. Clinicopathological parameters were evaluated using a chi-square test and logistic regression model in association with node pCR.

Results: The mean age at diagnosis was 47.9 years in all patients. Eighty-one (65.9%) patients were preoperative clinical T2 stage, 74 (60.2%) showed estrogen receptor (ER)-positivity, and 36 (29.3%) demonstrated HER2−positivity. A pCR of the axilla and breast was determined in 56 (46%) and 40 (31.7%) patients, respectively. Breast Pcr rate is significantly associated with age≤50 at diagnosis, ER(−),PR(−) and higher Ki-67 proliferation. Axillary pCR rate is significantly associated with age at diagnosis of 50 or less, smaller primary tumor size at diagnosis, tumor responsiveness to neoadjuvant chemotherapy, estrogen hormone receptors-negativity, higher Ki-67 proliferative index at diagnosis, and subtypes of HER2−enriched or triple negative breast cancer. When these factors entered logistic regression model, tumor response( SD+PD vs CR+PR: OR 8.603, P=0.007), Ki67((−) vs (+): OR 7.157, p=0.009), ER status((+) vs (−) : OR 4.943, P=0.036), pre-operation tumor size(>2cm vs ≤2cm: OR 5.116, p=0.044), HER2 status( (−) vs (+): OR 5.029,p=0.046) remained to be significant for the prediction of axillary pCR, favorable nodal response.

Conclusion: Our study suggests that primary tumor response to neoadjuvant chemotherapy is significantly associated with favorable nodal response. The factors of tumor and nodal response were similar. There are many issues remained to be determined yet.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-18.
P3-14-20: Concomitant Taxane-Anthracyclin Regimen for Neoadjuvant Chemotherapy of Primary Breast Cancer: Experience from a Cohort of 223 Patients Treated in a Single Institution.
Authors: Coquan E , Guizard A-V , Heutte N , Bor C , Allouache D , Delcambre C , Switsers O , Guilloit J-M , Leiber N , Delier T , Levy C
Published: June 2012

Background: Neoadjuvant chemotherapy (NAC) may be an alternative to mastectomy for localized breast cancer ineligible for breast conservation. The optimal schedule (sequential versus concomitant) remains controversial. Based on encouraging results of a phase 2 study (Luporsi E. et al, ASCO 2000) a concomitant docetaxel (D) and epirubicin (E) neoadjuvant combination is applied in neoadjuvant setting in our institution since 2001 for HER2−negative patients (pts). The results of this combination are presented, with a particular focus on pathological complete response (pCR) and conservation rate.

Methods: Between 2001 and 2010, 223 pts received NAC for a T2-T3 breast cancer initially ineligible for conservative surgery, but with hope of breast conservation in case of downstaging by pre-operative medical treatment. Six cycles of D (75mg/m2) and E (75mg/m2) were administered every 3 weeks before surgery, with prophylactic support of G-CSF in order to reduce the risk of febrile neutropenia and to maintain the dose-intensity of the NAC. All patients eligible for breast conservation after NAC underwent lumpectomy, the others were treated by mastectomy. In all cases, an axillary dissection was performed. After lumpectomy all patients received radiation therapy, after mastectomy RT was limited to high risk of loco-regional relapse. Patients with positive hormonal receptors (HR+) received hormonal therapy. Results were analyzed in term of breast conservation rate (BCR), pathologic response rate (pCR defined as no residual invasive tumour in breast and axilla, according to Sataloff's classification) and safety.

Results: Mean age of patients was 49,6 years (range: 26–71). Median clinical tumor size was 40mm (range 20–110). Histological subtypes were:78,0 % ductal, 15,3 lobular, 1,8 % ductal/lobular and 4,9 % other types. SBR grading was: grade I: 14,3 %, grade II: 46,2 %, grade III: 33,2 % and 6,3 % unspecified. 77,3 % were HR+, 19,7 % of tumours were triple negative (HER2 unknown for 38 cases). A breast conservation was achievable for 73,5% of patients, the pCR rate was 20,6%. At a median follow up of 48 months, 31 pts relapsed: 9 pts (4%) experienced a local relapse, 5 regional and 28 distant recurrences occured. Additional data about safety and survival will be provided for the meeting.

Conclusions: For HER2−negative tumours, 6 cycles of a concomitant taxane-anthracyclin pre-operative combination allowed a 20,6% pCR rate, slightly lower than obtained with 8 cycles of a sequential regimen in several published trials. However breast conservation rate was similar with a low risk of local recurrence. According to these results, concomitant cytotoxic combination is an acceptable option for neoadjuvant treatment of breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-20.
P3-14-21: Neoadjuvant Therapy Response, Subtype and BRCA Status in an Underserved Population.
Authors: Tripathy D , Ahmed S , Bahl P , Wang Y , Ji L , Ricker C , Weng Grumley J , Liu SV , Sener SF , Klipfel N , Kaur C
Published: June 2012

Background

Preoperative (neoadjuvant) chemotherapy is typically used for larger operable breast cancer cases, and the degree of pathological response correlates with long term outcome. Therapeutic response also depends on biological and molecular subtype and is increasingly studied in the research setting to identify prognostic biomarkers and potential therapeutic targets. Little is known about the interactions of neoadjuvant response with biomarker subtypes and genetic predisposition in underserved and minority populations.

Methods: IRB approval was obtained to capture demographic, clinicopathological and genetic testing data on patients diagnosed with invasive breast cancer and treated with preoperative chemotherapy and definitive surgery between 2005 and 2010 at Los Angeles County Medical Center, which serves a primarily Hispanic and indigent population. Treatment followed NCCN guidelines with the exception that not all patients with HER2+ disease received trastuzumab. Genetic counseling and testing has been available at this center since 2007. Pathological complete response (pCR) was defined as no residual invasive disease in breast or nodes. Chi-square or Fisher's Exact test was used to examine associations between pCR and clinical factors, and logistic regression analyses were applied to assess each variable's contribution to pCR.

Results: Among 104 patients, of whom 79% were Hispanic, the overall pCR rate was 27%. Significantly higher pCR rates were seen in age ≥50, clinical N0, HER2+, triple negative, and lumpectomy cases. No differences in pCR rate was seen in Hispanics vs. others, Grade III vs. I and II or in the 9 BRCA mutations carriers among 45 tested compared to no mutation or those not tested. Of the 43 patients with HER2+ disease, the pCR rate was higher in the 32 patients who received trastuzumab (pCR 50.0 vs. 27.3%). Subset pCR rates and odds ratios (OR) of achieving pCR are shown below:

Conclusions: In this underserved cohort, with 43% undergoing genetic testing, significantly higher pCR rates were seen in HER2+ and triple negative and lumpectomy cases, with a trend seen in older patients and smaller tumors. There was an unexpected trend of lower pCR rate seen in BRCA mutation carriers (pCR OR 0.33), albeit with small numbers. No differences were seen in Hispanic cases compared to other ethnicities. Further tissue analyses are planned to examine established and novel markers and to define exploratory markers that could be used for decision-making and target discovery in larger datasets within this population.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-21.
P3-14-23: Response to Neoadjuvant Chemotherapy and Survival in Japanese Patients with Triple-Negative Breast Cancer.
Authors: Ohtani S , Kochi M , Ito M , Takada S , Matsuura H , Higaki K
Published: June 2012

Background

Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2)expression. In this study, we compared response to neoadjuvant chemotherapy and survival between Japanese patients with TNBC and non-TNBC.

Patients and Methods

Analysis of a prospectively collected clinical database was performed. We analyzed 335 Japanese patients who received neoadjuvant chemotherapy at Hiroshima City Hospital for stage I-III breast cancer from 2002–2010. Clinical and pathological parameters, pathological complete response (pCR) rates, survival measurements, and organ specific relapse rates were compared between with TNBC and non-TNBC.

Results: 21.1% had TNBC. Patients with TNBC compared with non-TNBC had not significantly higher pCR rate (28% v 19%; p=0.09), similar disease progression-free survival (DFS) rate (p=0.59), but decreased overall survival (OS) rate (p=0.02). TNBC was associated with increased risk for visceral metastasis (p<0.0001) and shorter postrecurrence survival (p=0.017). If pCR was achieved, patients with TNBC and non-TNBC had similar survival. In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (p=0.01). Conclusion: TNBC patients with pCR after neoadjuvant chemotherapy have excellent survival. However, TNBC patients with RD have significantly worse survival, compared with non-TNBC patients with RD. Japanese patients with TNBC have also similar results with those in other ethnic group reported before.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-23.
P3-14-26: The Effect of Biologic Subtype in Patients Treated with Neoadjuvant Chemotherapy: A UAB Experience.
Authors: Keene KS , De Los Santos JF , Meredith R , Hinton B , Li Y , Krontiras H , Bland K , Carpenter JT , Forero A
Published: June 2012

Purpose: Previous studies have suggested that the pre treatment clinical stage drives loco-regional recurrence (LRR), distant metastasis (DM) and survival in patients treated with neoadjuvant chemotherapy. This retrospective analysis was performed to look at the effect of biologic subtype on patient outcomes.

Methods: Between 1999 and 2005, 115 patients treated with neoadjuvant chemotherapy, surgery, and +/−radiation therapy at UAB were identified. Patient, tumor, and treatment characteristics were recorded. Pathologic complete response was defined as resolution of both invasive disease and DCIS in both the primary and nodal disease. Survival was measured using the Kaplan Meier statistics. Univariate and multivariate analyses of covariates associated with LRR, DM, progression-free (PFS) and overall survival (OS) were performed. Results: The mean age was 49 years, with a mean follow-up of 5.8 years. Subtype distribution was as follows: 52 luminal A, 17 luminal B, 36 triple negative, 9 Her2+ and one patient with an unknown biologic subtype. Distribution of clinical stage was as follows: 40 IIA, 34 IIB, 26 IIIA, 10 IIIB, and 5 IIIC. Tumors were down-staged following neoadjuvant therapy as follows: 18: pCR, 6: residual DCIS, 17: I, 38: IIA, 11: IIB, 13: IIIA, 5: IIIB, and 7: IIIC. Pre-treatment clinical stage did not significantly influence LRR, DM or progression free and overall survival; however, final pathologic T, N and group stage were associated with both progression free, p=0.003, 0.011, 0.005 and overall survival, p=0.02, 0.037, and 0.009. Complete resolution of tumor by mammographic or MR imaging to neoadjuvant chemotherapy, was associated with an increased overall survival, p=0.0025. Univariate analysis did not show a significant effect of biologic subtype, age, grade, use of radiation therapy or anti-hormonal therapy.

Discussion: In this retrospective series, response to chemotherapy and the final pathologic stage, representing the volume of residual disease, were important predictors of survival. Further study to determine factors predictive of chemotherapy response is needed.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-26.
P3-16-06: Phase II Trial of TS-1 in Combination with Oxaliplatin (SOX) in Patients with Metastatic Breast Cancer (MBC) Previously Treated with Anthracycline and Taxane Chemotherapy [TORCH] [Korean Cancer Study Group (KCSG) BR07-03].
Authors: Im S-A , Oh D-Y , Lee KS , Ahn J-H , Shon J , Ahn JS , Kim JH , Han SW , Lee MH , Lee KE , Lee K , Kim HJ , Keam B , Kim S-Y , Kim SB , Im YH , Ro J , Park H-S
Published: June 2012

Background

Oxaliplatin, a platinum analogue, is an active drug in advanced anthracycline and taxane-pretreated breast cancer patients as a single agent and with 5-fluorouracil (5-FU) combination. TS-1 was developed by the scientific theory of both potentiating antitumor activity of 5-FU and reducing gastrointestinal toxicity. This trial was performed to evaluate the efficacy and safety of TS-1 in combination with oxaliplatin in metastatic breast cancer (MBC) patients previously treated with anthracycline and taxane chemotherapy.

Methods: Between October 2007 and October 2009, MBC patients were enrolled in this prospective multicenter trial. Eligible criteria included age ≥18 years, at least one measurable lesion, prior treatment with anthracycline and taxane chemotherapy, and ECOG Performance Status 0–2. TS-1 40 mg/m2 b.i.d. on days 1–14 with oxaliplatin 130 mg/m2 on day 1 were administered every 3 weeks till disease progression. Primary end-point was response rate, and secondary end-points were time-to-progression (TTP), overall survival (OS), duration of response (DOR) and toxicities. Response was evaluated every 6 weeks according to the RECIST criteria v. 1.0 and toxicity was assessed with NCICTCAE v.3.0.(ClinicalTrials.gov identifier NCT00527930).

Results: A total of 87 patients were enrolled. Median age was 48 years (range 30–71 years). Nineteen patients (21.8%) had de novo stage IV and 68 patients (78.2%) had recurrent disease. Thirty-five patients (40.2%) received two-lines of prior chemotherapy in palliative setting. Forty-eight patients (55.2%) had ≥ 3 disease sites. Fifty-four patients (62.1%) were hormone receptor positive, and 25 patients (28.7%) were triple negative. Five patients received prior anti-HER2 therapy. A total of 525 cycles were administered (median 6 cycles, range: 1 ∼ 22+ cycle). In per-protocol analysis, overall response rate was 38.5% (95% CI: 27.7−49.3) (CR 0%, PR 38.5%) and disease control rate (CR, PR, and SD) was 67.9% (95% CI: 57.5−78.3). Median TTP, OS, and DOR were 6.0 months (95% CI: 5.1−6.9 months), 19.4 months (95% CI: not estimated), 6.6 months (95% CI: 3.7−9.6 months), respectively. RR was not different by triple negativity (39.1% in TNBC vs. 38.2% in non-TNBC, P=0.361). TTP was not different according to the number of prior chemotherapy regimens. Reported grade 3 or 4 toxicities (per cycle) were neutropenia (10.3%), thrombocytopenia (5.5%), diarrhea (1.9%), vomiting (1.9%), and stomatitis (0.2%). There was no treatment-related death.

Conclusions: SOX is an effective regimen in anthracycline and taxane pretreated MBC patients with manageable toxicities.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-06.
P3-18-03: In Vitro Potency of mTOR Kinase (TOR1/TOR2) Inhibitor, INK128 in ER+ and HER2 Overexpressing Breast Cancer Cells.
Authors: De P , Sun Y , Dey N , Leyland-Jones B
Published: June 2012

Background

Persistent activation of the PI3K-AKT-mTOR1/2 signaling pathway drives aberrant cell growth and proliferation in a variety of tumor types including breast tumors. Recent works have demonstrated a strong association between mutational activation of PIK3CA or loss of function of PTEN and resistance to therapies targeted against the ER or HER2 pathway.

Purpose: Since PI3K-AKT-mTOR is one of the major signaling pathways responsible for the progression of breast cancer, as well as appears to be upregulated during development of the resistance to the endocrine and trastuzumab treatment, suppression of this pathway by administration of INK128 (mTOR1/2 kinase inhibitor) may therefore be efficacious in ER+ and HER2+ breast cancer models.

Experimental Design: To examine this possibility, INK128 was treated in ER+ (MCF7, BT483, T47D and MDA-MB-415), trastuzumab-sensitive HER2+ (BT474), trastuzumab-resistant (BT474HR), and PIK3CA mutated/HER2+ breast cancer cells (HCC1954 and UACC893). We have tested the effects of INK128 on the, (a) cell survival/proliferation, (b) integrin-directed cell migration, and small GTP-ase activation, (c) downstream signaling pathways for proliferation and apoptosis, and (d) 3D ON-TOP-colony formation.

Results: Treatment of ER+ and HER2+ cell lines with INK128 in vitro showed that 1) cell lines were sensitive to single agent INK128 with 50% inhibitory concentration ranging from 15 nM-10 μM in ER+ cell lines and 20 nM −50 nM in HER2+ cell lines, 2) 70–80% anti-proliferative activities were observed on 3D-ON TOP colony formation assay in both ER+ and HER2+ cells, 3) INK128 dose- and time-dependently blocked downstream effectors of mTOR1/2 pathway i.e. p-AKT (at Ser473), p-P70S6K, p-S6 ribosomal protein, p-4EBP1(interestingly, potent inhibition was also observed in cell line resistant to trastuzumab), 4) INK128 also blocked AKT phosphorylation at Thr308 (although in lesser extent than at Ser473), 5) rapalog-mediated AKT activation was blocked when cells were treated with INK128, 6) in ER+ cell lines INK128 more efficiently blocked p-4EBP1 than rapalog, 7) HER3 expression was significantly upregulated following treatment of trastuzumab-resistant cells (BT474HR) with INK128, and 8) integrin-dependent cell migration was significantly abrogated with INK128 in association with inhibition of RAC1-GTP.

Conclusion: Our preclinical in vitro data demonstrate that concurrent inhibition of mTOR1and mTOR2 is likely to be a more effective in both ER+ and HER2+ breast cancer cells than the inhibition of mTOR1 alone. We are currently studying the effect of INK128 on downstream apoptotic signals in ER+ and HER2+ cell lines, the results of which will be presented in the meeting.

INK128 was generously supplied by Inkellikine, San Diego, CA.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-18-03.
P3-18-06: AEZS-131 – A Highly Selective ERK-Inhibitor: Characterization and Preclinical Testing in Triple Negative Breast Cancer (TNBC).
Authors: Engel JB , Seipelt I , Hönig A , Hahne JC , Teifel M
Published: June 2012

Introduction: Overexpression of MAPK has been detected in 34 % of TNBC and has been found to be associated with anthracycline resistance (1). AEZS-131 is a highly selective orally active ERK1/2-inhibitor, which has shown in vivo activity (first in class) in colon cancer. The following study explores mode of action and efficacy in models of TNBC.

Study design: AEZS-131 was tested in a kinase panel of 36 STK, 26 TK and 7 PIK to check for selectivity. Inhbition of Rsk-phosphorylation (cellular substrate of ERK) was evaluated by western blot analysis. Mode of action was explored by cell cycle FACS-analysis. Cleavage of PARP was explored by Western blot. Cytotoxic efficacy was evaluated in 5 TNBC, of which 2 had mutations in the MAPK signal transduction pathway lines, by MTT assay. Additionally it was explored if inhibition of classical apoptosis could abrogate the effect of AEZS-131.

Results: AEZS-131 selectively inhibited ERK with an IC50<4nM. Phosphorylation of Rsk-1 the cellular substrate of ERK was inhibited with an IC 50 of 158 nM. AEZS-131 induced cell cycle arrest in G1 dose-dependently and cleavage of PARP. EC 50 was 0,739 μM for MDA-MB-231 (Ras-mutated), 0,137 μM for MDA-MB-435s (B-RAF mutated), 17,5 μM for MDA-MB-468 (PTEN loss), 25 μM for HCC 1806. HCC 1937 were not inhibited by the compound. Of note, inhibition of classical apoptosis did not alter the cytotoxic effect of the compound in MDA-MB-468 and HCC-1806 cells.

Conclusions: AZS-131 was shown to selectively inhibit ERK at low nM concentrations and to induce G1-arrest. Accordingly, the cytotoxic effect most pronounced in TNBC cell lines with mutations in the MAPK pathway. If classical apoptosis is inhibited, cytotoxic effects remain unchanged, suggesting that AEZS-131 can also induce nonclassical forms of programmed cell death. AEZS-131 should be further explored in TNBCs with overexpression of MAPK or mutations in the MAPK-pathway.

*Æterna Zentaris GmbH, Frankfurt/M, Germany.

(1): MAPK overexpression is associated with anthracycline resistance and increased risk for recurrence in patients with triple-negative breast cancer.

Eralp Y, Derin D, Ozluk Y, Yavuz E, Guney N, Saip P, Muslumanoglu M, Igci A, Kücücük S, Dincer M, Aydiner A, Topuz E.

Ann Oncol. 2008 Apr;19(4):669–74.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-18-06.
P4-01-15: Alteration of Y-box Binding Protein-1 Expression Modifies the Response to Endocrine Therapy in Estrogen Receptor Positive Breast Cancer.
Authors: Ito T , Kamijo S , Izumi H , Kohno K , Ito K-I
Published: June 2012

Y-box binding protein-1 (YB-1) plays an important role in tumor progression and drug resistance. This study examined whether YB-1 is involved in the alteration of response to endocrine therapy in ER-positive breast cancer cells. MCF7 cells that stably expressed YB-1 (MCF7-YB-1) and vector control cells (MCF7-vector) were established. These cells were used to analyze the expression of the factors related to the ER and growth factor receptor signaling pathways, response to the antiestrogens (tamoxifen and fulvestrant), and estrogen responsive element (ERE) activity. The effect of knocking down endogenous YB-1 expression was tested in wild-type MCF7 cells. In addition, the expression of the YB-1 and the factors related to the ER and growth factor receptor signaling pathways were evaluated in the clinical breast cancers treated with preoperative chemotherapy. The expression of HER2, AIB1, p-Erk and c-Myc were increased in the MCF7-YB-1 cells. In contrast, knocking down of YB-1 decreased the expression of these factors, but increased the expression of ERα in the wild-type MCF7 cells. Furthermore, sensitivity to antiestrogens was decreased in the MCF7-YB-1 in comparison to those in the MCF7-vector cells. In the MCF7-YB-1 cells, the expression levels of p-Erk and c-Myc were continuously upregulated when the cells were treated either with tamoxifen or fulvestrant. The ERE activity was decreased in the MCF7-YB-1 cells in comparison to the MCF7-vector cells, and the ERE activity of the MCF7-YB-1 cells was inhibited by fulvestrant at a lower concentration than that which inhibited the ERE activity of the MCF7-vector cells. In the ER-positive clinical breast cancers treated with preoperative chemotherapy, significantly more of the specimens that showed increased or positive nuclear YB-1 expression after the chemotherapy were positive for HER2 expression. These data suggest that alteration of YB-1 may modify the crosstalk between the ER pathway and HER2 pathway in ER-positive breast cancer cells, and consequently may alter the response to endocrine therapy in these cells.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-15.
P4-01-19: SRC-1 Expression Is a Prognostic Factor of Breast Cancer-Specific and Disease-Free Survival in Inflammatory Breast Cancer.
Authors: Arias-Pulido H , Ahmed RD , Chaher N , Vargas J , Joste N , Lomo L , Qualls C , Azziez S , Terki N , Bouzid K , Prossnitz E , Royce M
Published: June 2012

Background: Steroid receptor coactivator (SRC-1 to 3) proteins drive nuclear receptor transcriptional activity by modulating transcriptional processes such as chromatin modification, transcription initiation, chain elongation, and RNA splicing. In patients who display resistance to endocrine treatment, SRC-1 has been implicated in the conversion of tamoxifen anti-agonist activity to its agonist profile. SRC-1 expression is a prognostic of DFS in breast cancer, but its role in inflammatory breast cancer (IBC) remains unknown.

Materials and Methods: SRC-1 protein levels were measured by immunohistochemistry in 103 IBC and 11 normal, non-cancer related samples, diagnosed at the Centre Pierre & Marie Curie (Algiers, Algeria). Staining results were correlated with protein levels of ER, PR, and HER2, and clinico-pathological variables, breast cancer-specific (BCSS) and disease-free survival (DFS), and response to tamoxifen treatment.

Results: SRC-1 was positive in all normal breast tissue, as well as in 66% of IBC samples. SRC-1 positivity was associated with worse OS (P<0.001) and DFS (P=0.004). SRC-1 expression correlated with worse BCSS (P=0.011), and marginally with DFS (P=0.046) in tamoxifen-treated patients, but strongly with DFS (P=0.007) in patients who received no endocrine therapy as indicated by Kaplan-Meier and log-Rank analyses. Multivariate analysis showed that SRC-1 (Hazard Ratios (HR): 5.2; 95%CI: 2.0−13.6; P<0.001) and Her2 (HR: 3.1; 95%CI: 1.2−8.1; P=0.02) expression were independent prognostic markers of BCSS. SRC-1 (HR: 4.8; 95%CI: 1.9−12.2; P<0.001), Her2 (HR: 2.4; 95%CI: 1.0−5.7; P=0.05), and hormone treatment (HR: 0.4; 95%CI: 0.2−0.8; P=0.01) were independent prognostic markers of DFS.

Discussion: Determining prognosis and predicting response to endocrine treatment is of paramount importance in the search for personalized treatment. SRC-1 expression predicts worse OS, DFS, and, similar to non-IBC, predicts DFS independently of endocrine therapy. This study highlights the importance of SRC-1 expression as a strong prognosticator of BCSS and disease recurrence in IBC patients. *Supported by an UICC ICRET Fellowship (ICR/09/043 to Dr. Chaher) and by New Mexico State IBC funding (New Mexico Senate Bill 532).

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-19.
P4-02-01: Bis(2-Ethylhexyl) Phthalate: A Potential Endocrine Disruptor Confer Letrozole Insensitivity and Induction of Aromatase Activity in Breast Cancer Cells.
Authors: Nair HB , Bhaskaran SS , Krishnegowda NK , Tekmal RR , VandeBerg JL
Published: June 2012

Exposure to endocrine disrupting compounds (EDC's) is an important determinant of mammary gland development and mammary tumor pathogenesis. The risk of breast cancer in adulthood is known to be influenced by environmental factors experienced as a fetus. Fetal exposure to dietary factors or certain pharmaceuticals and environmental chemicals that affect or mimic steroid hormones increase predisposition to breast cancer. The mechanisms by which EDC's alter epigenetic programming, differentiation and deregulation of ductal branching of mammary glands are poorly understood. A high ratio of estrogen receptor a (ERα) to ERβ has been recently found to be associated with poor prognosis and aggressive disease in breast cancer patients. Preliminary studies from our laboratory revealed that bis(2-ethylhexyl) phthalate (DEHP) is a possible EDC which induces cell proliferation in T47D, MCF7, MCF7/Aro breast cancer cells in vitro and confers insensitivity to letrozole, a third generation aromatase inhibitor. DEHP increased cell proliferation (MTT assay) in a dose dependent manner and was non toxic to T47D, MCF7 and MCF 7 Aro cells. 1, 10 and 100 nM concentrations of DEHP up regulated ERα and down regulated ERβ at the mRNA level. Hypermethylation in the estrogen receptor beta (ERβ) promoter was observed after treatment with 1nM DEHP for 24 h, suggesting that DEHP alter epigenetic programming through changes in the DNA methylation to modify the chromatin structure and change the accessibility of DNA to transcription factors. When breast cancer cells were treated with letrozole (200nM and DEHP (1nM) together, they survived, whereas those treated with letrozole alone did not survive. Aromatase mRNA and enzyme levels were higher in the DEHP treated cells by comparison with sham control MCF7/Aro cells. Nonmalignant MCF-10A breast epithelial cells showed a proliferation advantage (MTT assay) by up regulation of ERα as well as aromatase expression when treated with 1nM DEHP. Aromatase transgenic mice treated with 10mg/Kg b.wt of DEHP over a period of 30 days resulted in the excessive ductal branching density and epithelial outgrowth in the mammary gland. The present data suggest that dietary accumulation of DEHP through plastic food containers, water bottles, etc. may contribute to risk of hormone sensitive breast cancer in women and chemoinsensitivity and or drug resistance in breast cancer patients.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-01.
P4-02-07: Influence of the Progesterone Receptor on the Prognosis of Breast Cancer in Interaction with Other Prognostic Factors.
Authors: Salmen JC , Fasching PA , Hepp P , Jueckstock J , Haeberle L , Mohrmann S , Beckmann MW , Hartmann A , Wachter DL , Friese K , Janni W , Rack B
Published: June 2012

Introduction: The expression of the estrogen receptor (ER) and/or the progesterone receptor (PR) is a predictive factor for the response to endocrine treatment and to chemotherapy in primary breast cancer. Knowledge about the prognostic relevance of the PR is rare and partly controversial. Aim of this retrospective study was to analyze the prognostic relevance of PR.

Methods: Between 1995 and 2008, data from 5,144 patients with heterogeneously treated primary breast cancers have been collected in 3 German university hospitals.

The laboratories used immunhistochemical assays for the investigation of the ER and PR.

The PR-expression was correlated with patient and tumor characteristics.

For each outcome parameter overall survival (OS), distant disease free survival (DDFS) and local recurrence free survival (LRFS) cox proportional hazad models were built. Furthermore the effect of the PR status was analyzed according to tumor subgroups.

Results: PR status was associated with a more favourable OS, DDFS and LRFS in the univariate analysis. PR remained an independent prognostic factor for OS and DDFS but not for LRFS in the cox proportional hazard model.

For OS and DDFS the prognostic effect of PR seemed to be consistent among the subgroups and was significant for most of them. Comparing subgroups there was a difference between the HR for ER negatives and ER positives. In ER negative tumors the prognostic effect of the PR seemed to be larger (HR=0.40; 95%CI: 0.25−0.63) than in ER positives (HR=0.68; 95%CI: 0.53−0.87). For all other subgroups there seemed to be no interaction between PR status and the other prognostic factors.

Conclusion: PR positivity results into a similarly favourable prognosis in ER negative and ER positive patients. ER positivity alone seems not to be sufficient to define a group of patients with the most favourable prognosis. On the contrary, patients with ER positive, PR negative tumors have a signicantly deteriorated prognosis and seem to be a patient group, which should be investigated concerning drug resistance mechanisms.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-07.