bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-08-14: Could the preoperative systemic therapy be a risk factor for breast cancer-related lymphedema in stage II/III breast cancer?
Authors: Jung SY , Song EJ , You JY , Lee MH , Kwon Y , Ko KL , Park IH , Lee KS , Ro J , Lee S , Kang H-S , Lee E , Shin KH
Published: August 2014

Background: The breast cancer-related lymphedema (LE) has been known to be closely related to axillary lymph nodes dissection (ALND), chemotherapy, and radiation therapy. In this study, we evaluated whether the sequence of systemic chemotherapy and surgery could be a predictive factor in stage II/III breast cancer.

Methods and Materials: A total of 867 patients with stage II/III breast cancer, who underwent curative surgery with adequate systemic therapy from 2004 to 2009, were retrospectively analyzed. Adjuvant chemotherapy (ACT) was performed in 571 patients (65.9%) and preoperative systemic chemotherapy (PSC) in 296 (34.1%). We evaluated the incidence of LE by clinicopathologic factors and treatments.

Results: At a median follow-up of 5.1 years (range, 3.0-8.3 years), 360 patients (41.5%) had experienced LE, 244 patients have retained LE (permanent LE), and 116 patents were normalized. The overall 5-year cumulative incidence of LE was 17%. LE occurred in 188 patients (32.9%) in patients with ACT, 172 patients (58.1%) with PSC (P<0.001), permanent LE in 121 (21.2%) with ACT, 123 (41.6%) with PSC (P<0.001), respectively. Multivariate analysis showed that PSC (hazard ratio [HR], 1.65; P<.001), radiotherapy (HR, 2.24; P<0.01), ALND (HR, 1.41; P = 0.04), and nodal stage (HR, 1.93; P = 0.04) were independent risk factors for LE occurrence. For the permanent LE, PSC (HR, 1.44; P = 0.05), radiotherapy (HR, 2.79; P<0.01), ALND (HR, 1.77; P<0.01), and nodal stage (HR, 3.01; P = 0.02) showed the associations.

Conclusions: The risk factors associated with LE were advanced stage, ALND and radiotherapy. PSC was one of predictors for transients LE. However, further evaluation should be done whether it is a risk factor for permanent LE.

This research was supported by National Cancer Center Grant NCC-1210181-2 by the National Cancer Center, Republic of Korea.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-14.
Abstract P3-09-17: One year of adjuvant hormone therapy does not increase patient fatigue: Results of a prospective early stage breast cancer trial
Authors: Lower EE , Kennedy D , Adams P
Published: August 2014

INTRODUCTION: The diagnosis and treatment of breast cancer may alter a patient's mental and physical quality of life. Estrogen effects on the brain may be neuroprotective or detrimental, and adjuvant endocrine therapy may influence cognitive functions including fatigue. We previously reported that three months of adjuvant hormone therapy was not associated with change in fatigue. The purpose of this study was to prospectively determine the incidence of fatigue in early stage breast cancer patients during one year of adjuvant hormone therapy. METHODS: Seventy-four consecutive patients of a single medical oncologist with newly diagnosed hormone dependent breast cancer prescribed adjuvant hormone therapy enrolled in this prospective study. Data collected included age, race, menopausal status, breast cancer stage, body mass index, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT)-F, Fatigue Assessment Scale (FAS), short form 36 (SF-36), and cognitive failure questionnaire (CFQ). All tests were administered by one nurse prior to hormone initiation (0 mo) and after 3, 6, 9, and 12 months (mo) of therapy. Statistical analysis was performed using Student t test for paired data with a p value of <0.05 considered significant. RESULTS: Prior to starting therapy, a third of patients had a FAS score of >22, consistent with moderate to severe fatigue. After 12 months of therapy, 52 patients (13 premenopausal, 39 postmenopausal) were still receiving adjuvant hormone therapy and had completed serial testing. Twenty patients received chemotherapy prior to institution of hormone treatment. There were no significant changes in FACIT-F, FAS, SF-36, or CFQs scores during the first 12 months of treatment.

 0 mo3 mo6 mo9 mo12 moFACIT-F44 (7-52)*42 (3-52)43 (3-52)43 (2-52)44 (6-52)FAS17 (10-43)18 (10-48)17 (10-48)20 (10-48)19 (10-50)Weight, lb.159 (102-256)162 (102-258)161 (102-258)163 (102-263)164 (101-258)SF-36 Total72 (12-100)68 (15-99)83 (15-99)76 (15-99)82 (7-100)CFQ70 (39-94)69 (34-92)68 (34-94)67 (28-96)70 (20-96)* Median (Range)

Although during the first six months, a small but significant increase in body weight occurred, there was no significant difference between the initial and 12 month body weight. CONCLUSION: Prior to adjuvant hormone therapy institution, breast cancer patients often have significant problems with fatigue. However, the first 12 months of adjuvant hormone therapy does not appear to affect fatigue or cognitive failure.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-17.
Abstract P3-11-04: The effect of group intervention therapy for young breast cancer patients under 35 years old
Authors: Kitano A , Hosaka T , Iwata T , Osaka W , Kitagawa H , Ohde S , Yamauchi H
Published: August 2014

Background: Coping with cancer plays an important role in cancer survivorship. Especially in young patients, coping is significant because of anxieties regarding fertility, body image, heredity, symptoms of premature menopause, and psychosocial stress. According to previous studies, the group intervention therapy is effective in improving emotional difficulties for breast cancer patients. However, there is few demonstrating the efficacy of group intervention for young breast cancer patients.

Methods: Since September 2010, we have conducted a clinical trial of a group intervention, facilitated by breast surgeons, psycho-oncologists, and nurses, for young breast cancer patients who were diagnosed under 35, or 36 years old due to enrolling period, and they had no metastasis. at St Luke's International Hospital (SLIH) in Tokyo, Japan. Each group consisted of 7 to 10 breast cancer patients, who received five weekly sessions. We evaluated the changes in coping strategies, emotional levels, and quality of life (QOL) before, after and 6 month after the group intervention, by using three scales: MAC (Mental Attitude to Cancer) for coping, POMS (Profile of Mood States) for emotional states, and FACT-B (Functional Assessment of Cancer Therapy-Breast) for QOL. MAC scale includes five coping strategies such as Fighting Spirit(FS), Hopelessness(H), Anxious Preoccupation(AP), Anxiety(A), and Fatalism(F). This is an interim report of this clinical trial. Paired T-test was used to statistical evaluation.

Results: At this point, 65 young patients finished the group intervention. Complete data were taken from 61 patients for evaluating score changes between before and after the group interventions. POMS and FACT-B score improved statistically (p = 0.004, p = 0.003). Among MAC's five components, Hopelessness and Anxious Preoccupation improved statistically (p<0.01, p<0.001).

Discussion: This study suggests that the group intervention is promising to improve emotion states, QOL, and coping strategies for young breast cancer patients.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-11-04.
Abstract P3-13-01: Primary efficacy endpoint analysis of the CARIN trial: Capecitabine (Cap) and bevacizumab (Bev) with or without vinorelbine (Vin) in first line metastatic breast cancer (MBC)
Authors: Welt A , Lerchenmüller C , Decker T , Marschner N , Salat C , Hegewisch-Becker S
Published: August 2014

Background:

In RIBBON-1, the combination of Bev with Cap as 1st-line therapy for MBC significantly improved progression-free survival (PFS) compared with Cap alone, with limited impact on tolerability. Vin and Cap are active agents with few overlapping toxicities. The combination of both cytotoxic drugs in phase I/II trials showed good tolerability and promising clinical activity. The CARIN trial aims to further improve efficacy by adding Vin to Cap/Bev to establish a less toxic alternative to taxane-based 1st line therapy.

Patients and Methods:

CARIN is a multicenter randomized study comparing the efficacy of Cap plus Bev versus the same regimen combined with Vin. From 04/2009 until 10/2012 598 pts in 61 participating centers were randomized (1:1) to receive Cap 1000 mg/m2 bid days 1–14 + Bev 15 mg/kg q3w (Arm A) or Cap/Bev combined with Vin 25 mg/m2 days 1+8 (Arm B). Randomization was stratified by prior therapy with anthracycline and/or taxane (yes/no) and hormone receptor status (ER/PR +/-). Treatment was continued until progression or unacceptable toxicity. Key eligibility criteria included Her-2 negative metastatic or locally recurrent disease, no prior palliative chemotherapy for MBC, ECOG ≤2, and absence of brain metastases. Primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate, overall survival, and safety & tolerability. Baseline demographics, prior therapy and disease characteristics were well balanced. 21.5% of pts had triple negative BC, 10.6% had bone metastases only. Progression free survival data for the two treatment arms will be compared using a log-rank test. The influence of pretreatment, hormone receptor status and predictive variables on progression free survival will be analyzed within a cox regression model.

Results:

Data Cleaning and analysis will be complete by October 2013 and results for the primary endpoint PFS and secondary endpoints will be presented at the meeting.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-01.
Abstract P3-14-11: Microarray data analysis and long term outcomes of NCIC-CTG MA.22: Neoadjuvant epirubicin and docetaxel with pegfilgrastim support for locally advanced breast cancer
Authors: Trudeau M , Chapman J-A , Guo B , Clemons M , Dent R , Jong R , Kahn H , Shepherd L , Pritchard K , Xu J , O'Brien P , Parissenti A
Published: August 2014

Background: 93 patients were enrolled in sequential phase 1 and 2 trials of epirubicin (E) and docetaxel (D) given at 3 (cohort A) or 2 weekly (cohort B) intervals. We previously reported clinical (93%) and pathologic response rates (pCR 7%) as well as the association of fall in tumour RNA integrity (RIN) with response (ASCO 2010). Here we report the results of microarray analysis of tumor specimens pre-and mid-treatment to determine genes which are differentially expressed in different groups. Methods: 6 core biopsies were collected for all patients pre-, mid- and post-treatment with ED. 3 cores were used for standard pathologic assessment while 3 were used for gene expression assessment using Agilent full genome microarrays. Pre- and mid-treatment cores were used with Agilent Feature Extraction Software to assess microarrays; and baseline continuous (% positive) immunohistochemical ER, PR, HER2, and Topo2 were investigated by schedule and dose. RNAs with RIN > = 5.0 were subjected to microarray analysis. NIH BRB array tools were used for investigations of differential gene expressions. K-M curves were generated for the phase 2 cohorts for disease free (DFS) and event free survival (EFS), and for ER− PR− and ER or PR+ subgroups. Results: Of the 93 patients, 47 were in cohort A and 46 in cohort B. Median overall survival was 6.34 years on study. DFS at 50 months was 55% for A (phase 2) and 67% for B (phase 2), while EFS was 55% for A and 63% for B. For ER or PR+ DFS and EFS were 60% and for ER− PR− DFS and EFS were 63%. 134 arrays were available in total: 57 from A, 68 from B with 11 reference breast tumour RNAs for standardization. Patients with and without microarrays were not significantly different. Pre-treatment, we found 3 differentially expressed genes in A and 6 in B between patients who did and did not have RIN > = 5.0 at mid-treatment. Comparing CR to non-CR (PR, SD, PD), 40 genes were found for A and 2 genes for B. Many genes were also differentially expressed in A and B when analyzed by pathologic factors ER, PR, HER2, Topo2, schedule and dose. Mid-treatment, 4,365 genes in A and 18,770 genes in B were significantly different from pre-treatment. Conclusion: At 50 months, DFS was 55% for 3 weekly and 67% for 2 weekly schedules of ED. The genes identified in each cohort pretreatment will be investigated further for relevance to predicting sensitivity or resistance to E or D.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-11.
Abstract P3-14-15: Nabrax: Neoadjuvant therapy of breast cancer with weekly nab-paclitaxel: Final safety of GEICAM 2011-02
Authors: Martin M , Antolin S , Anton A , Plazaola A , Garcia-Martinez E , Segui MA , Sanchez-Rovira P , Esteban C , Garcia-Valdes E , Calvo L , Quindos M , Carrasco E , Rodriguez-Martin C , Chacon JI
Published: August 2014

Aims: nab-paclitaxel is an innovative chemotherapy that consists of nano-particles of human serum albumin bound paclitaxel. It exploits the role of albumin as the natural carrier of hydrophobic molecules in human to increase paclitaxel delivery to tumor cells. Weekly nab-paclitaxel showed a superior efficacy compared to every 3-weeks docetaxel in a randomized phase II study in metastatic breast cancer (Gradishar JCO 2009, Clin. Breast Cancer 2012). This single arm phase II trial has been designed to evaluate the activity and safety of weekly nab-paclitaxel as neoadjuvant treatment of early stage breast cancer patients with positive estrogen receptors and negative HER2.

Methods: Stage II-III patients were included and treated with nab-paclitaxel weekly at a dose of 150 mg/m2 on days 1, 8 and 15 every 4 weeks for 4 cycles. Following chemotherapy, patients undergo surgery and adjuvant therapy (with radiation, chemo and endocrine therapy) under the investigator criteria. The primary objective is to determine the residual cancer burden class III as measured by the Symmans criteria (JCO 25:4422,2007). Secondary objectives include pathological complete response, overall response, invasive disease free survival, safety and potential correlative biomarkers.

Results: Eighty-three patients have been recruited in the study in 13 Spanish institutions. Here we report safety data from 77 patients. Median age was 48 years, 62% were postmenopausal and 94% had ECOG PS 0; most patients were stage II (23% IIa and 36% IIb). A total of 259 cycles have been administered to date; 47 patients completed 4 cycles as planned, 5 patients discontinued treatment early (due to grade 2-3 sensory neuropathy in 4 patients), the remaining patients are still under treatment. The treatment was delayed in 8.1% of patients; nab-paclitaxel doses were omitted and reduced in 3.9% and 9.7% of cycles respectively, for a relative dose intensity of nab-paclitaxel of 97.3%. The most frequent reasons for dose modifications were neutropenia (5.4%) and neuropathy (2.7%). The main grade 2/3 adverse events are described in table 1.

Table 1Related adverse events.Per patient (N = 74)Per Cycle (N = 259)NCI-CTCAE vs 4.0. (>5% grade 2-4)Grade 2, N (%)Grade 3, N (%)Grade 2, N (%)Grade 3, N (%)Leukopenia6 (8.1)1 (1.4)11 (4.2)1 (0.4)Neutropenia17(23)7 (9.5)30 (11.6)9 (3.5)Alopecia47(63.5)—121 (46.7)—Fatigue11 (14.9)2 (2.7)17 (6.6)2 (0.8)Neuropathy: Sensory17 (23)2 (2.7)25(9.6)5 (1.9)Musculoskeletal Pain11 (14.9)0 (0)13 (5.0)0 (0)

Conclusions: Neoadjuvant therapy with weekly nab-paclitaxel at dose of 150 mg/m2 on days 1, 8 and 15 every 4 weeks was well tolerated. Final safety data for the entire treated patients will be mature and presented at the meeting.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-15.
Abstract P3-14-18: Dose-dense neoadjuvant chemotherapy in locally advanced breast cancer. Long term results of a cooperative retrospective study
Authors: Ionta MT , Notari F , Murgioni S , Cugudda S , Marongiu M , Solinas C , Pala L , Lepori S , Demurtas L , Olmeo N , Valle E , Sarobba G , Frau B , Pusceddu V , Defraia S , Serci C , Fanzecco M , Tanca FM , Atzori F
Published: August 2014

BACKGROUND: Dose-dense chemotherapy results in better overall (OS) and disease free survival (DFS) in women with hormone receptor-negative early breast cancer as shown with a systematic review and meta-analysis by Bonilla et al (JNCI 2010). Aim of our study was to compare neoadjuvant dose-dense chemotherapy with standard dose schedule in T4 patients in terms of DFS and OS, according to hormone-receptor status.

PATIENTS AND METHODS: we analysed, retrospectively, 160 consecutive T4 patients, of median age 52 ys (range 29-73) who received neoadjuvant anthra-based chemotherapy with and without taxanes, observed from 1989 to 2009; 74 patients (46%) received dose-dense schedule (q14) and 86 (54%) conventional dose (q21); 68 (42%) patients were ER-negative (32 q14; 36 q21) and 92 (58%) patients were ER-positive (42 q14; 50 q21). No Trastuzumab was allowed during neoadjuvant treatment.

RESULTS: at a median follow-up of 130 months (range 8-241 months), overall, 10 y DFS was 41.9% and 30.2% on q14 and q21 schedules, respectively (p = 0.085); 10 y OS was 48.6% on q14 and 44.2% on q21 schedule, (p = 0.343). ER-negative patients who received q14 schedule had better DFS (46.9%) than those on q21 schedule (16.7%), (p = 0.007) [Relative Risk 0,63 and Odds Ratio 0,22] and better OS (50%) than those on q21 schedule (30.6%) (p = 0.083) [Relative Risk 0,61 and Odds Ratio 0,44]. DFS and OS did not differ on q14 and q21 schedules in ER- positive patients.

CONCLUSIONS: Our findings are consistent with published data and suggest that there is no appreciable survival benefit from increasing dose density among T4 ER-positive patients. Dose-dense neoadjuvant chemotherapy may be justified in LABC patients with T4 ER-negative tumors.

 DFS OS  q 14q 21pq 14q 21pER-46,9%16,7%0.00750%30,6%0.083ER+38,1%40,0%0.51247,6%54,0%0.344

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-18.
Abstract P3-15-04: A French prospective pilot study to identify dihydropyrimidine dehydrogenase (DPD) deficiency in breast cancer patients receiving capecitabine
Authors: Milano G , Ferrero J-M , Thomas F , Bobin-Dubigeon C , Merlin J-L , Pinguet F , Ferrand C , Boyer J-C , Romieu G , Bachelot T , Pivot X , Dieras V , Largillier R , Mousseau M , Goncalves A , Roche H , Bonneterre J , De Clercq B , Etienne-Grimaldi M-C
Published: August 2014

Background: Health Authorities point out that DPD deficiency confers a significant risk of major toxicity for patients receiving capecitabine. Identification of at-risk patients is thus of major concern. This multicentric prospective study of the French GPCO group (Groupe de Pharmacologie Clinique Oncologique, Unicancer) evaluated the sensitivity, specificity and predictive values of DPD phenotyping and genotyping to predict severe cap-related toxixity in metastatic breast cancer patients.

Methods: 303 patients were included between February 2009 and February 2011 (15 institutions). Eighty-eight% received capecitabine as monotherapy, 28% were treated as first line (mean dose at 1st cycle 1957 mg/m2/d). Pre-treatment uracil (U, physiological DPD substrate) plasma concentration was measured in 286 patients (HPLC assay). DPD genotyping (IVS14+1G>A, 2846A>T, 1679T>G, 464T>A) was performed on 281 patients. Severe toxicity (G3-4 CTCAE v3 criteria) was measured over cycles 1-2.

Results: Grade 3-4 toxicity (diarrhea, vomiting, hematoxicity, hand-foot syndrome) has been observed in 19.6% of patients (one toxic death). A marked trend for higher U concentrations has been noted in patients developing severe toxicity vs those who didn't (median 12.7 ng/ml (Q1-Q3 9-17) vs median 10.2 ng/ml (range 8-13), respectively, p = 0.014). However, ROC curve has showed that this difference was too small for use as a reliable toxicity predictor. The patient with toxic death had an elevated U concentration at 17 ng/ml. Among the 7 patients with a DPD mutation (3 pts IVS14+1, 3 pts 2846A>T, one 1679T>G, all heterozygous), 5 developed severe toxicity (including the toxic death, 2846A>T), one did not, and the last one was not documented. Relative risk for developing severe toxicity was 4.60 in mutated patients vs wild-type patients (95%CI 2.95-7.16, p = 0.001); positive and negative predictive values were 83.3% and 81.9%, respectively; specificity was 99.5% and sensitivity was 9.8%.

Conclusions: Breast cancer patients harbouring a DPD variant allele are at risk to develop severe, up to lethal, capecitabine-related toxicity. Pre-treatment U measurement remains to be more firmly established as a reliable predictor of capecitabine toxicity. These observations are of major interest for breast cancer patients candidate for capecitabine therapy.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-15-04.
Abstract P4-01-05: 3’-deoxy-3’-[18F]fluoro-thymidine (18F-FLT) positron emission tomography (PET): An accurate and effective tool for assessing tumor response in breast cancer
Authors: Couturier O , Rousseau C , Pierga J-Y , Berriolo-Riedinger A , Alberini J-L , Girault S , Fumoleau P , Brain E , Abadie-Lacourtoisie S , Vera P , Liehn J-C , Olivier P , Uwer L , Cachin F , Sagan C , Bouchet F , Lebas N , Mesleard C , Fourme E , Martin A-L , Lovinfosse P , Lacœuille F , Campone M
Published: August 2014

Objectives : A French multicenter study was promoted by the national French cancer federation (Unicancer R&D) to assess the potential of [18F]FLT (positron emission tomography (PET) biomarker of proliferation)to manage breast cancer neoadjuvant chemotherapy (NAC). The main objective was to compare changes in tumor [18F]FLT uptake to histopathological changes induced by NAC, assuming an arrest of tumor growth related to the effectiveness of NAC.

Methods : 97 patients (age 48.6 +/- 10.2 y.) were included in 13 nuclear medicine centers. All patients were eligible to anthracycline-based NAC for a de novo unifocal breast cancer (ductal n = 84, lobular = 11, other type = 2; stage II n = 75, stage III n = 21 et stage IV n = 1). 90 patients underwent a baseline PET before the onset of NAC (PET1) and a final PET after the end of NAC and before surgery (PET3). PET acquisitions were performed 60±7min after FLT injection. SUVmax (maximum standardized uptake value), SUVpeak (1 cm3 ROI including pixel max) and SUV41 (isocontour 41% of pixel max) were computed. Changes in SUV on PET3 vs PET1 were analyzed in relation to histopathological findings at the end of NAC (Sataloff criteria).

Results : Tumor FLT uptake decreased markedly between TEP1 and TEP3 (SUVmax = 6.2±4.8 vs 1.3±1.2 respectively; SUVpeak = 4.6±3.2 vs 0.9±0.9; SUV41 = 3.6±2.8 vs 0.8±0.7). Total or near-total therapeutic effect (grade A) were obtained in 20 patients, more than 50% therapeutic effect but less than total or near-total effect (grade B) in 37 patients, less than 50% therapeutic effect but visible effect (grade C) in 22 patients, or no therapeutic effect (grade D) in 11 patients. SUVmax decreased dramatically (87.5%) to background levels in all patients with a complete response (grade A). Overall, changes in SUV differed depending on the type of histological response (p<0.01) i.e. SUVmax changes were more pronounced as pathological responses were good: 61% for grade D; 65.7% grade C and 69.8% grade B. The same results were obtained with the two other SUV types.

Conclusions : Pathologic response to NAC in breast cancer can be assessed accurately by FLT.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-05.
Abstract P4-01-07: Evaluation of FLT PET-CT as an imaging biomarker of proliferation in primary breast cancer
Authors: Woolf DK , Beresford M , Li SP , Sanghera B , Wong WL , Amin V , Ah-See M-L , Miles D , Sonoda L , Detre S , Dowsett M , Makris A
Published: August 2014

Background

[18F]flurothymidine (FLT) is proposed as an positron emission tomography (PET) imaging biomarker of proliferation for breast cancer. The aim of this prospective study was to assess the feasibility of FLT PET-CT as a technique for predicting response to neoadjuvant chemotherapy (NAC) in operable breast cancer and to compare baseline FLT to Ki-67.

Methods

20 patients with primary breast cancer were recruited into this study and 19 received NAC with FEC (n = 6) or FEC-T (n = 13). A baseline FLT PET-CT scan was performed and repeated before the second cycle of chemotherapy. Expression of Ki-67 in the diagnostic biopsy was quantified after being stained by Dako Ki67 MIB-1 antibody and% positive cells scored. From the FLT PET-CT scans standardized uptake value maximum (SUVmax) were calculated.

Results

All 20 patients completed the baseline scan and 17 completed the second scan. Baseline Ki-67 results were available for 19 patients. Median age was 52 years (range 32 to 67), 12 patients were ER/ PR +ve, 6 Her-2 +ve and 6 triple negative.

Mean baseline SUVmax was 7.3 (range 2.92 to 13.87) and 4.62 (range 1.79 to 14.15) post 1 cycle of NAC (range 7 to 14 days), representing a drop of 2.68 (36.3%). Mean baseline Ki-67 was 32.23 (range 2.3 to 68.4). Pearsons correlation showed a significant correlation between pre-chemotherapy Ki-67 and SUVmax of 0.604 (p = 0.006).

7 out of 17 (41%) patients achieved near pCR or pCR (pathological responders) after NAC and all of these had a reduction in SUVmax with a mean percentage value of –36.5% (range -0.5% to -62.5%). 10 out of 17 (59%) patients were non-responders and 8 of these had a reduction in SUVmax with a mean percentage value of -36.2% (range 11.3% to -70.7).

Conclusions

Baseline SUVmax measurements of FLT PET-CT were significantly related to Ki-67 suggesting that it is a proliferation biomarker. However, in this series neither the baseline value or the change in SUVmax after one cycle of NAC were able to predict response as most patients had a sizeable SUVmax reduction.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-07.
Abstract P4-04-04: Targeted resequencing of germline PTEN-negative patients with Cowden disease reveals alternate mechanism of molecular alteration
Authors: Sevenet N , Gourdon S , Lafon D , Dupiot-Chiron J , Geneste G , Jones N , Bonnet F , Longy M
Published: August 2014

Introduction

Cowden disease belongs to the PTEN hamartoma tumor syndrome (PHTS) group, defined by germline PTEN heterozygous inactivation. Describing the PTEN germline mutation in Cowden disease patients is of particular importance for their breast cancer and thyroid carcinoma predisposition evaluation.

Material & methods

Targeted resequencing was done on germline DNA of 22 index cases patients with a Cowden disease clinically well established since they do not demonstrate any PTEN mutation analyzed using our current screening method (EMMA, Enhanced Mismatch Mutation Analysis, similar to high resolution melting). The 565 exons of 34 genes of interest together with the entire genomic locus of PTEN were captured using the SureSelect oligonucleotide library capture (Agilent technologies). The bioinformatics resources Suredesign, Ensembl human genome v70 and a UCSC repeat masker least stringent were used to create the capture design. This gave us 28405 unique 120-mers oligonucleotide probes which were duplicated 1 to 16 times depending on the GC content or the size of the targeted regions (maximum boosting performance criteria). For each gene of interest, an exon of the surrounding gene was also captured in order to define the extent of gross gene rearrangement. Samples were prepared according the manufacturer's recommendations.

Results

Each of the 22 Cowden disease patients demonstrates a mean rate of 70 intronic mutations in the entire genomic locus of PTEN. All of those for which the minor allelic frequency is unknown, were subjected to splicing site bioinformatic prediction. For one patient, the prediction reveals the apparition of a splicing site in a deep intronic mutation of the large intron 1 of PTEN. Furthermore, next generation sequencing (NGS) seems to be more sensitive than our current screening method since for two patients, a germline mosaic exonic heterozygous inactivating mutation of PTEN was detected and confirmed by Sanger sequencing on different biological samples. The level of mosaicism was evaluated by NGS at 3 to 12% depending on the sample and confirmed by pyrosequencing. In addition, some mutations were identified in exons of genes encoding proteins of the PI3Kinase pathway, which could be involved in disease belonging to the PHTS group. With an increasing sensitivity, NGS is a powerful tool to detect low frequency variant. This could used to explain at a molecular level Cowden disease with no initially detectable PTEN mutation. Clinical and biological rationale, bioinformatics workflow and comprehensive results will be presented.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-04.
Abstract P4-05-09: Estrogen receptor (ER) mRNA expression and molecular subtype distribution in breast cancers that are ER-negative but progesterone receptor-positive by immunohistochemistory
Authors: Iwamoto T , Matsuoka J , Nogami T , Motoki T , Shien T , Taira N , Niikura N , Hayashi N , Doihara H , Symmans WF , Pusztai L
Published: August 2014

Purpose: We examined Estrogen receptor (ER) mRNA expression and molecular subtypes in breast cancers that are Progesterone receptor (PR) positive but ER negative by immunohistochemistry (IHC) to assess if these cancers molecularly resemble true ER positive cancers.

Patients and Methods: Patients were those with newly diagnosed ERBB2-negative breast cancer treated with neoadjuvant chemotherapy containing sequential taxane and antheracycline-based regimens (then endocrine therapy if ER-positive by IHC). ER and PR status was determined by IHC in 501 primary breast cancers in routine pathology laboratory. Gene expression profiling was done with the Affymetrix U133A gene chip (Gene Expression Omnibus number: GSE25066). We compared expressions of ESR1, MKI67 mRNA and molecular subtypes determined by the PAM 50 classifier between IHC-ER-positive/PR-positive (n = 223), ER-positive/PR-negative (n = 73), ER-negative/PR-positive (n = 20), and ER-negative/PR-negative (n = 185) cancers. We also plotted survival curves by ER and PR status based on IHC.

Results: ER or PR positivity by IHC was defined ≥ 1% staining. ER positivity by ESR1 mRNA expression was defined as > 10.18 previously published. Among the IHC-ER-negative/PR-positive, ER-positive/PR-negative, and both ER/PR-positive, and ER/PR-negative patients, 25%, 79%, 96% and 12% were positive by ESR1 mRNA expression, respectively. The average ESR1 expression was significantly higher in the ER/PR-positive and ER-positive/PR-negative cohorts compared with the ER-negative/PR-positive or ER/PR-negative cohorts. The average MKI67 mRNA expression was significantly higher in the ER-negative/PR-positive and ER/PR-negative cohorts. Among the ER-negative/PR-positive patients, 15% were luminal A, 5% were Luminal B, and 65% were basal like; among the ER-positive/PR-negative patients, 59% were luminal type. The relapse free survival rate of ER-negative/PR-positive patients was equivalent to ER/PR-positive or ER-positive/PR-negative, and significantly better than that of the ER-negative/PR-negative cohort.

Conclusion: Only 20-25% of the ER-negative/PR-positive tumors show molecular features of ER-positive cancers (i.e high ER mRNA expression and luminal molecular class). These cancers also have higher proliferation rate than ER-positive cancer. However, the survival of these cancers with only chemotherapy is similar to ER-positive cancers with chemotherapy and endocrine therapy, and is better than ER-negative cancers. The contribution of endocrine therapy to this good outcome is to be invested in the future.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-09.
Abstract P4-06-02: Changes in intrinsic subtype of breast cancer during tumor progression in same patient
Authors: Kim C , Kim A
Published: August 2014

Introduction: Hormone receptor(ER, PR), Epidermal growth factor receptor 2 (HER2) and Ki67 are important prognostic factors and key variables in classification of intrinsic subtype which is essential for selection of adjuvant therapy in breast cancer management. There have been previous reports that instability of hormonal and HER2 status during tumor progression. Recently breast cancer treatment guidelines recommended using intrinsic subtype for treatment option. Especially intrinsic subtypes were determined by using 4 immunohistochemical (IHC) assays that is ER (estrogen receptor), PR (progesterone receptor), HER2 and Ki67. The purpose of this study was to investigate whether the intrinsic subtype changes as tumor progresses from ductal carcinoma in situ (DCIS) to lymph node metastasis

Methods: 90 cases of breast cancer were constructed with 2-mm core tissue microarrays (TMA). All cases simultaneously have DCIS, invasive carcinoma (IDC) and lymph node metastasis. IHC and Silver in situ hybridization (SISH) assay was performed on TMA. All of the cases after 2005 had informed consent from the patients for using their medical information and tumor tissues. Evaluation of hormone receptors expression was based on the Allred scoring method. For HER2, membranous staining was evaluated according to the guidelines of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP). Using the results of the immunohistochemical analyses, tumors were classified into four subtypes. To define luminal A type is an ER positive and/or PR positive, HER2 negative and Ki67 low. As well as luminal B type is an ER positive and/or PR positive, HER2 positive or Ki67 high. HER2 type is HER2 positive, ER negative and PR negative and Ki67 low or high. Basal like type is classified as exhibited ER, PR, and HER2 negative.

Results: Of the 90 cases, the lesions with DCIS showed 39 were luminal A, 24 were luminal B, 19 were HER2, and 8 were basal like. The lesions with IDC showed 31 with luminal A, 26 with luminal B, 23 with HER2, and 10 with basal like. Also, 28 were luminal A, 29 were luminal B, 21 were HER2, and 12 were basal like for lymph node metastasis. Overall 25% breast cancer change their intrinsic phenotype during progression.

Conclusions: This study demonstrated that a subset of breast cancers can change their intrinsic subtype during cancer progression. These changes have huge impact on patient prognosis and management because each subtype have own different optimized treatment options according to St Gallen and NCCN guideline.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-06-02.
Abstract P4-06-04: Effect of genomic heterogeneity on breast cancer progression and metastatic spread
Authors: Ellsworth RE , Valente AL , Blackburn HL , Decewicz A , Deyarmin B , Mamula K , Shriver CD , Ellsworth DL
Published: August 2014

Purpose: DNA fingerprinting has revealed discordant patterns of chromosomal alterations in primary breast tumors (PBT) compared to matched metastatic axillary lymph node tumors (MLNT); however, whether these genetic differences reflect the timing of dissemination of cells with metastatic potential from the primary tumor, intratumoral heterogeneity of the primary breast tumor, or independent seeding of lymph nodes with metastatic cells remains unclear.

Patients and Methods: From the 30 node-positive patients evaluated in this study, allelic imbalance (AI) data was generated using 52 microsatellite markers from 5-19 areas of each PBT as well as from available MLNT. Data were analyzed using pairwise correlations, ANOVA and PHYLIP.

Results: The frequency of genomic changes was significantly higher (P<0.001) in PBT areas (13%) than MLNT (9%). No two PBT areas had identical patterns of AI and the percent concordance (PC) of AI events between tumor regions ranged from 0-65% (average 33%). Of the 196 MLNT from 28 patients, PC between MLNT from the same patient ranged from 0-88% (average = 32%). Neither the overall frequency of AI nor the PC differed significantly between sentinel (SLN) and non-SLNs. Phylogenetic analysis revealed that within patients, many MLNT appeared to be descended from different areas of the PBT, but patterns of descent were complex.

Conclusions: Both PBT and MLNT are characterized by extensive molecular heterogeneity, MLNT appear to originate from different areas of the PBT, and SLN metastases are not genomically more advanced than non-SLN metastases. These data suggest that metastatic dissemination may be influenced by both spatial and temporal factors, with cells with metastatic potential colonizing lymph nodes throughout the development of the PBT, and that SLN metastases do not appear to be a source of metastatic cells for non-SLN but rather MLNT arise by independent colonization.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-06-04.
Abstract P4-06-10: Breast cancer subtypes in Indian women: A comparison of clinicopathological features and outcome
Authors: Mane AD , Deshmukh SP , Nag SM , Guha A , Sane SP , Zade BP
Published: August 2014

Background:

Immunohistochemical markers are often used to classify breast cancer into different subtypes that have distinct biological behaviour. The aim of this study was to estimate the distribution of the different subtypes of breast cancer based on immunohistochemistry, in the Indian population and determine their associations with clinicopathological features and outcome.

Methods:

This is a 5 year retrospective study of 521 breast cancer patients to compare the clinicopathological features and survival of four subgroups – Luminal A (ER/PR +, Her 2 neu –), Luminal B (ER/PR +,Her 2 neu +), Her 2 enriched (ER-/PR -, Her 2 neu +)and triple negative(ER-,PR-,Her 2 neu -).

Results:

Majority (43.8%) of the patients were in luminal A subgroup. Luminal B patients were 14.8%, Her 2 enriched group were 16.1% and triple negative patients were 25.3%. Median follow up was 34 months. Patients in luminal A subgroup were more likely to be postmenopausal, have smaller size tumours, have grade I/II tumours and have better survival (OS-91.06%), though it was not statistically significantly different from other subgroups.

Clinicopathological characteristics and outcome according to breast cancer subtypes  Luminal ALuminal BTriple negativeHer 2 neup valueMenopausal statusPre39.09%13.71%30.46%16.75%  Post46.60%15.43%22.22%15.74%0.159Type of surgeryBCS44.25%19.54%22.99%13.22%  MRM41.78%12.50%27.96%17.76%0.099Type of chemotherapyAnthra based36.68%11.32%29.25%20.75%  Taxane + Anthra based36.97%14.29%29.41%19.33%0.923Tumor size in cmsLess than 254.55%12.12%21.21%12.12%  2-546.52%13.52%27.27%12.83%  > 528.57%9.52%33.33%28.57%0.065OutcomeAlive without disease44.41%15.59%24.75%15.25%  Alive with disease42.67%16.0%25.33%16.0%  Death35.56%15.56%26.67%22.22%0.924Grade of tumorI71.43%17.86%3.57%7.14%  II51.19%11.95%22.87%13.99%  III23.21%16.96%39.29%20.54%<0.001table 1

The triple negative subgroup was more likely to be premenopausal (p value 0.036, odds ratio 0.611, CI 0.394-0.949), have larger and grade III tumours and had worse overall survival (OS-88.46%, odds ratio 1.32, 95%CI 0.602-2.39). Patients in Her 2 enriched group also had the bad prognostic features like larger tumour size, higher grade and worst survival (OS-85.07%, odds ratio 1.78, 95% CI 0.767-4.163).However the outcome was not statistically significantly different for all the subgroups.

Conclusions:

In this tertiary cancer care hospital retrospective study of breast cancer patients in India, according to the luminal subtypes, luminal A had better prognostic features and survival compared to other subgroups.Incidence of triple negative patients was high, who were mainly premenopausal.Her 2 enriched group had the worst survival among all.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-06-10.
Abstract P4-07-04: A distinctive miRNA profile highlights breast cancer in very young women (BCVY) as a new molecular subgroup
Authors: Peña-Chilet M , Martinez MT , Perez-Fidalgo JA , Peiro-Chova L , Bermejo B , Ferrer J , Alonso E , Burgues O , Bosch A , Lluch A , Ribas G
Published: August 2014

Background: Although less frequent (1% of all breast cancer) than in older women, breast cancer (BC) in very young women (BCVY),(≤35 years old) often exhibits larger tumor sizes, high pathological grade, high proliferation percentage, nodal involvement, and greater HER2+ percentage, usually associated with a poorer prognosis. BC and BCVY might arise as different disease entities derived from different underlying mechanisms.

MicroRNAs (miRNAs) are short RNA molecules with post-transcriptional regulatory function, usually silencing targeted mRNAs. Recently, miRNA profiling has arisen as major approaching study technique, demonstrating a widespread miRNA deregulation in various tumor types.

In this study we offer a miRNA profile of a subset of BCVY patients and evaluate whether there are any miRNA deregulated pointing out some pathway to better understand the ongoing mechanism and characterize BCVY as a new molecular entity.

Material and methods: We performed a comprehensive study of miRNA expression using miRNA Affymetrix 2.0 array. We extracted RNA from FFPE tumor tissue of both 44 BC patients ≤35years (BCVY) and 46 older than 45years in two age groups (45-65 and >65), we used normal breast tissue as control and evaluated the differences in expression of each age group. We tried to validate most interesting miRNA by qRT-PCR. We performed enrichment analysis of multiple miRNA target genes (DIANA mirpath) to search for putative pathways that could be deregulated by the miRNAs.

Results: We obtained a differential and unique miRNA expression profile of 121 miRNAs (p-value<0.05), 96 of those with FDR<0.05. After hierarchical clustering, samples were unsupervised grouped according to their age, neither by subtype nor by tumor characteristics. Of the 11 miRNA selected for validation, we were able to validate differences in the expression of 6 miRNAs: miR-1228*, miR-3196, miR-1275, miR-92b, miR-139, miR-1207, moreover, all of the miRNAs maintained the expression's trend. The validated miRNAs pointed out pathways related with cell motility and invasion (adherens junction, chondroitin sulfate biosynthesis, cell adhesion molecules) and cell proliferation (calcium signaling, wnt signaling).

Conclusion: We performed a comprehensive study of the miRNA expression on a total of 89 BC patients, detecting a differential molecular profile in BCVY patients, suggesting that there might be a different underlying mechanism and that BCVY could be identified as a different entity.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-04.
Abstract P4-07-10: MicroRNAs as biomarkers and therapeutic adjuvants for the prognosis and treatment of drug-resistant breast cancers
Authors: Chang Y-F , Pannerdoss S , Zoghi B , Jatoi I , Rao MK
Published: August 2014

Intrinsic and acquired resistance to antineoplastic agents continues to be a major clinical impediment to successful treatment of cancer in general, and breast cancer in particular. For example, about 40% of ER-positive metastatic breast tumors fail to respond to tamoxifen therapy, and of those that initially respond many will eventually develop resistance. Similarly, taxanes used as a first-line chemotherapy agent will have a response rate of 50%, which comes down to 20–30% in second- or third-line chemotherapy; nearly half of the treated subjects do not respond to it and suffer side effects. These facts underscore the importance of understanding the mechanism of resistance, which is crucial for the optimal systemic therapy of breast cancer. Unfortunately, in spite of extensive inquiry in this field, little is known about the key molecules/signaling pathways that regulate this phenomenon. Recently, we have discovered that small non-coding RNAs, i.e. microRNA (miRNAs), may play a critical role in mediating drug resistance in breast cancers. We have identified miRNAs that are differentially expressed between drug-resistant and sensitive breast cancer cells. Specifically, we have combined a high-throughput screening platform with a library of chemically synthesized inhibitors for all known human miRNAs and identified specific miRNA that selectively sensitize/de-sensitize drug-resistant breast cancer cells to either tamoxifen or trastuzumab (herceptin), drugs that are commonly used as a first line treatment for ER-positive and Her2-positive breast cancers, respectively. We identified 10 and 12 miRNA inhibitors that sensitized resistant cells to tamoxifen and trastuzumab, respectively. Interestingly, expression of cognate miRNA/s that sensitize resistant tumors to drug-induced cell death in our screen was found to be lower in relapsed (drug-resistant) metastatic breast cancer patients compared to normal matched control. In addition to tumor tissues, the levels of sensitizer miRNA/s in the blood sera of relapsed metastatic breast cancer patients was found to be dramatically lower than that of normal healthy individual. These findings are significant as it suggests that miRNAs can be efficiently detected in blood serum and therefore, can be used as a potential biomarker for predicting treatment outcomes. In addition, miRNAs may provide novel therapeutic tools for the treatment of drug-resistant breast cancers.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-10.
Abstract P4-09-05: Preventive efficacy of the Chinese nutritional herb epimedium grandiflorum in a preclinical cell culture model for luminal A molecular subtype of breast cancer
Authors: Telang NT , Li G , Katdare M , Sepkovic DW , Bradlow LH , Wong GYC , Telang N
Published: August 2014

Background: The Luminal A molecular sub-type of clinical breast cancer expresses estrogen receptor (ER) and progesterone receptor (PR), but lacks the expression of HER-2 oncogene. This cancer sub-type responds to endocrine therapy involving the use of selective estrogen receptor modulators or inhibitors of estrogen biosynthesis. Conventional therapeutic options are frequently associated with acquired tumor resistance and systemic toxicity, and therefore, emphasize a need for identification of promising new non-toxic agents for secondary prevention. Nutritional substances that do not incur long-term toxicity represent ideal candidates. Nutritional herbs have been used in traditional Chinese medicine for a variety of health related issues, including prevention of breast cancer.

Methods: The present study utilized the human mammary carcinoma derived ER+/PR+/HER-2- MCF-7 cells as a model for the Luminal A breast cancer to examine the preventive efficacy of non-fractionated aqueous extract from Epimedium grandiflorum (EG), a popular Chinese nutritional herb. Anchorage dependent growth, cell cycle progression, cellular metabolism of 17b-estradiol (E2), and anchorage independent colony formation represented the quantitative end point biomarkers for preventive efficacy.

Results: Maintenance of MCF-7 cells in a chemically defined serum depleted culture medium (serum 0.7%, E2<1 nM) retained their cellular growth promoting response to the physiologically relevant concentration range of 1 nM to 20 nM E2, exhibiting a 10.3% to a 91.9% increase in the viable cell number, respectively. A 7 day treatment of MCF-7 cells with EG resulted in a dose dependent inhibition of E2 promoted growth (EG IC50: 0.49%). At its maximum cytostatic concentration, EG inhibited cell cycle progression via G1 arrest, resulting in a 1.6 fold increase in the G1:S+G2/M ratio, and modulated the cellular metabolism of E2 in favor of formation of anti-proliferative metabolites 2-hydroxyestrone (2-OHE1) and estriol (E3), exhibiting a 5.1 and a 7.6 fold increase, respectively. In addition, EG produced a favorable 3.9 fold increase in the

2-OHE1: 16α-OHE1 ratio, an endocrine biomarker of breast cancer risk. A 21 day treatment of MCF-7 cells with EG produced a dose dependent inhibition in anchorage independent growth (EG IC50: 0.49%; IC90: 1.03%).

Conclusions: These data demonstrate the growth inhibitory effects of EG and identify clinically relevant mechanistic leads for its preventive efficacy. The present approach promises to facilitate identification of new efficacious herbs for the secondary prevention of the Luminal A subtype of clinical breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-09-05.