bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-11-04: Chemotherapy Induces Neuroinflammation and Cognitive Deficits in Female Mice
Authors: Jarrett BL , Lustberg MB , Hinzey A , Stuller KA , Shapiro CL , DeVries C
Published: August 2014

Introduction: Advances in cancer detection and treatment have substantially increased the survival rate for breast cancer patients. Chemotherapeutic drugs, particularly anthracyclines, have potentially toxic side effects in the brain- impacting memory, processing time and verbal fluency. More than 30% of patients undergoing chemotherapy for breast cancer report cognitive deficits during and after treatment. Despite the high incidence and significant impact on quality of life, little is known about the cause of the cognitive deficits and no effective treatment currently exists. Our hypothesis is that chemotherapy-induced neuroinflammation impairs cognition.

Methods: Adult female BALB/C mice were ovariectomized and then two weeks later injected intravenous (IV) with a single dose of chemotherapy (45 mg/m2 doxorubicin + 450 mg/m2 cyclophosphamide) or vehicle (n = 10–12/group). The mice were trained for three trials per day across six days in the Barnes Maze, a well-characterized spatial memory task.

Results: Both the chemotherapy-treated and vehicle-treated mice were able to acquire the task by the final day of training. However, the vehicle-treated mice reached asymptotic performance after fewer training sessions than the chemotherapy-treated mice. Furthermore, the chemotherapy-treated mice took significantly longer to find the escape box than the vehicle-treated mice on training days 2–5 (p < 0.05). In contrast, there were no group differences in overall locomotor activity level, suggesting that the observed difference in maze performance was not due to a fatigue. (p > 0.05) In addition, chemotherapy increased proinflammatory cytokine expression (TNF-α, IL-1β, and IL-6) in the hippocampus (p < 0.05), a region of the brain that is critical for spatial learning and memory. Likewise, microglia from chemotherapy-treated mice exhibited increased expression of MHCII and CD80 relative to vehicle-treated mice (p < 0.05), thereby suggesting a proinflammatory phenotype.

Conclusions: Together, these data suggest that the administration of doxorubicin and cyclophosphamide in doses that are approximately 25% lower than the typical dose for women treated for breast cancer, produce neuroinflammation, including microglia activation, increased proinflammatory cytokine expression and concomitant cognitive deficits in female mice. Additional studies will establish whether a causal relationship exists between chemotherapy-induced neuroinflammation and cognitive deficits. Identifying the mechanism through which chemotherapy induces cognitive deficits is the first step toward designing therapeutic interventions.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-11-04.
Abstract P2-11-06: Mortality among offspring of women diagnosed with breast cancer; a population based study
Authors: Verkooijen HM , Ang X , Liu J , Czene K , Salim A , Hartman M
Published: August 2014

Introduction: Survival after breast cancer has improved substantially over the past decades. As a result, an increasing number of breast cancer survivors is starting or extending their family post-diagnosis. We evaluated mortality risks of offspring from women with a history of breast cancer.

Methods: From the Swedish Multi-Generation Register and the Cancer Register we identified all 63,205 children whose mother had ever been diagnosed with invasive breast cancer. For these children, we calculated relative mortality risks as compared to the background population (Standardized Mortality Ratios [SMRs]). We compared SMRs according to the mother's parity status at diagnosis and timing of birth in relation to time of diagnosis, i.e. before (>1 year before), around (between 1 year before and 1 year after) and after (>1 year after) diagnosis.

Results: Children born around their mother's breast cancer diagnosis had an increased mortality risk as compared to the background population (SMR 2.70 95% CI [1.64–4.44]). This risk was particularly high for first-born children (SMR 11.07 (95% CI [2.09–27.13]), who had an absolute excess risk of 6.4% to die before the age of 5 years. Children born more than one year before or after their mother's breast cancer diagnosis had similar mortality risks as the background population.

Conclusion: Children born around their mother's breast cancer diagnosis have significantly increased mortality risks. Offspring of nulliparous women have a particularly high relative mortality risk, suggesting that pregnant breast cancer patients may be keen to keep their first child in spite of potential treatment toxicity.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-11-06.
Abstract P2-13-01: Impact of Body Mass Index (BMI) on the efficacy of aromatase inhibitors to suppress estradiol serum levels in postmenopausal patients with early breast cancer: a prospective proof of principle
Authors: Pfeiler G , Königsberg R , Hadji P , Fitzal F , Maroske M , Ban G , Zellinger J , Exner R , Seifert M , Singer C , Gnant M , Dubsky P
Published: August 2014

Background: BMI impacts on the efficacy of aromatase inhibitors (AIs) regarding disease outcome in patients with early breast cancer. We hypothesized that this clinical impact of BMI is driven by the inability of AIs to suppress estradiol (E2) serum levels to the same low level in obese compared to non-obese patients.

Methods: 68 postmenopausal ER positive patients with breast cancer, scheduled to receive anastrozole or letrozole as adjuvant endocrine treatment were prospectively included in this study. Serum was taken before (T1) and 3 months after start with aromatase inhibitors (T2). Serum levels of FSH, LH, E2, glucose and insulin were analyzed immediately in the clinical routine lab and in a dedicated central lab able to measure E2 in serum at low concentrations with high sensitivity.

Results: 40 patients were normal - or overweight (non-obese; BMI 18.5–29.9 kg/m2) and 28 patients were obese (BMI ≥ 30 kg/m2). A weak non-significant correlation between BMI and baseline E2 serum levels (r = 0.2, p = 0.2) translated into a strong negative, highly significant correlation between BMI and baseline FSH (r = −0.6, p < 0.01). After 3 months of AI treatment, a moderate correlation between BMI and E2 serum levels (r = 0.35, p = 0.05) and a moderate negative correlation between BMI and FSH (r = −0.34, p = 0.05) could be observed. Aromatase inhibitors significantly suppressed E2 serum levels in non-obese (T1: 18.9 pg/ml, T2: 9.0 pg/ml, p < 0.01) as well as in obese patients (T1: 20.2 pg/ml, T2: 12.5 pg/ml, p < 0.05). In addition an increase in FSH serum levels was observed in obese (T1: 50.0 mIU/ml, T2: 65.5 mIU/ml, p < 0.01) but not in non-obese (T1: 84.0 mIU/ml, T2: 84.6 mIU/ml) patients. However, after 3 months of AI treatment, E2 levels of obese patients were not at the same low level when compared to non-obese patients (E2 obese: 12.5 pg/ml vs. E2 non-obese: 9.0 pg/ml, p = 0.1). This difference translated into significantly lower FSH serum levels in obese compared to non-obese patients (FSH obese: 65.5 mIU/ml vs. FSH: 84.6 mIU/ml, p < 0.01). The significant effects of BMI on FSH serum levels could be detected both in the routine - as well as in the dedicated central lab.

Conclusion: AIs are less efficient at suppressing E2 serum levels in obese when compared to non-obese women. The observed effect may contribute to the survival disadvantage of obese patients in adjuvant AI trials. FSH serum levels should be validated as high sensitive surrogate parameters for estradiol serum level suppression by aromatase inhibitors in postmenopausal patients with breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-01.
Abstract P3-07-10: Effect of lifestyle and single nucleotide polymorphisms on breast cancer risk: A case-control study in Japanese women
Authors: Mizoo T , Taira N , Nishiyama K , Nogami T , Iwamoto T , Motoki T , Shien T , Matuoka J , Doihara H , Ishihara S , Kawai N , Kawasaki K , Ishibe Y , Ogasawara Y
Published: August 2014

[Background] Lifestyle, including diet and physical activity, and birth/breastfeeding history are known to affect the risk for breast cancer. A correlation between single nucleotide polymorphisms (SNPs) and breast cancer risk has also been suggested in some reports, but the gene-environment interaction with breast cancer risk has not been examined widely.

[Methods] The subjects were 476 breast cancer patients and 528 controls who attended a health check and had no history of breast cancer. Lifestyle was examined using a questionnaire with 48 questions about diet, physical activity, smoking habits, alcohol intake, and birth/breastfeeding history, etc. Based on past reports, we analyzed 6 SNPs (TNRC9-rs3803662, LSP1/11q-rs3817198, MAP3K1-rs889312, 8q24-rs13281615, 5p12-rs981782, and TGFβ1-rs1800470) using blood samples, and calculated age-adjusted odds ratios in a multiple logistic regression analysis.

[Results] The study was performed from December 2010 to November 2011. Lifestyle factors (age-adjusted odds ratio, [95% confident interval]) found to have a significant correlation with development of breast cancer included BMI (1.041, [1.00–1.08]), smoking history (2.28, [1.45–3.65]), small number of births (1.18, [1.05–1.34]), no exercise during leisure time (1.36, [1.06–1.77]), low intake of green and yellow vegetables (1.69, [1.01–2.85]), and low intake of mushrooms (1.58, [1.05–2.39]). Stratified analysis based on menopause status showed that smoking history (1.85, [1.00–3.49]) and low intake of green and yellow vegetables (2.5, [1.03–5.88]) were significant risk factors before menopause, and that smoking history (2.28, [1.45–3.65]), low intake of green and yellow vegetables (2.24, [1.09–4.68]), no exercise during leisure time (1.67, [1.19–2.36]), small number of births (1.49, [1.25–1.78]), and no breastfeeding history (1.03, [1.01–1.06]) were significant risk factors after menopause. The results of SNP analysis suggested that TNRC9-rs3803662 was a significant risk factor in women before menopause (2.29, [1.25–4.25]). However, in multivariate analysis including lifestyle factors and SNPs, only smoking history emerged as a significant risk factor in women before menopause.

[Conclusion] A correlation between lifestyle and breast cancer risk was found in this study, consistent with previous findings. Lifestyle and environmental factors such as births and breastfeeding may be more important than SNPs as risk factors for breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-10.
Abstract P5-18-15: Molecular effects of lapatinib in HER2 positive ductal carcinoma in situ (DCIS)
Authors: Estevez LG , Suarez A , Calvo I , Garcia E , Miro C , Durán H , Quijano Y , Perea S , Herrero M , Lopez-Rios F , Hidalgo M
Published: August 2014

Background: HER2 amplification is frequent in DCIS and is associated with poor prognosis features. This study aimed to determine the molecular effects in Ras/Raf/MAK and PI3K/AKT signaling pathway of the HER2 inhibitor lapatinib in patients with HER2 positive DCIS as well as correlation with radiological and pathological response.

Patients and Methods: Patients (pts) with HER2 positive DCIS received 1500 mg daily of lapatinib for 4 consecutive weeks prior to surgical resection. Changes in tumor volume were evaluated by MRI. The molecular effects of lapatinib on apoptotic level (TUNEL), cell proliferation (Ki67) and HER2 signaling pathway were determined in pre and post-treatment tumor biopsies.

Results: A total of 20 pts were included. Lapatinib was well tolerated with only minor and transient side effects reported. The agent effectively modulated HER2 signaling by affecting cell cycle kinetics through decreasing cytoplasm pERK1 in 11 pts with no change or slight increase activation in 5 pts. Of those 11 pts: eight had parallel inactivation of pHER2, two pts had paradoxical activation of pAkt and three pts had an increase in apoptotic level. In addition, seven pts also presented with decrease in MRI signal intensity and tumor size.

Conclusions: Four weeks of lapatinib for patients with HER2-positive DCIS result in significant antiproliferative changes through RAS/MAPK signaling pathway together with a decrease in MRI signal.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-15.
Abstract P6-05-02: Endocrine biomarkers in response to AR-inhibition with bicalutamide for the treatment of AR(+), ER/PR(−) metastatic breast cancer (MBC) (TBCRC011)
Authors: Gucalp A , Tolaney S , Isakoff SJ , Ingle J , Liu MC , Carey L , Blackwell KL , Rugo H , Nabell L , Forero A , Stearns V , Momen L , Gonzalez J , Akhtar A , Giri DD , Patil S , Feigin KN , Hudis CA , Traina TA
Published: August 2014

Background: Our group and others have identified a subset of ER/PR(−) breast cancers characterized by expression of the androgen receptor (AR) and androgen-dependent growth (Doane 2006). We conducted a proof-of-concept multicenter phase II study to test the efficacy of the AR-antagonist, bicalutamide for the treatment of AR(+) ER/PR(−) MBC (NCT00468715). Results of the primary endpoint, clinical benefit rate (CBR), were presented at ASCO (Gucalp 2012). Data for the impact of bicalutamide on circulating hormone levels in women are limited. Elevations in serum testosterone (T) and estradiol (E) have been observed for men treated with bicalutamide. We hypothesized comparable patterns of change in circulating endocrine markers in response to bicalutamide for women with MBC.

Methods: Patients (pts) with AR(+) (IHC ≥10%), ER/PR(−) (IHC <10%) MBC were eligible for treatment (tx) if ECOG performance status ≤2 and normal organ function regardless of menopausal status. There was no limit to prior tx except prior trastuzumab required if HER2(+). Tx consisted of bicalutamide 150mg orally daily in 28-day cycles (C). Toxicity assessed q4 weeks, response q12wks. Primary endpoint was CBR. Peripheral blood was collected for total and free T, E and sex hormone binding globulin (SHBG) at baseline, start of C2 (C2) and at end of study (EOS). Standard institutional assays were used. A Wilcoxon signed-rank test was done to compare baseline to C2 and EOS values.

Results: 26 patients with AR(+) ER/PR(−) MBC were treated on study. Evaluable number (n) of pts at baseline, C2 and EOS are 26, 26 and 19 respectively. Two pts remain on study. Menopausal status: pre=2, post=24. Baseline median total and free T and estradiol were consistent with expected norms, however a wide range was observed (Table). There were no significant differences observed for median free T, total T, E or SHBG between baseline and C2 or baseline and EOS. Changes in hormone levels could not be stratified by menopausal status or response to bicalutamide given small sample size. Given the wide range of baseline values, we examined the percent change for each endocrine biomarker from baseline to C2 and EOS. As shown in the Table, there was no difference in median percent change observed across time points for each biomarker.

Conclusions: No discernible patterns of change in T, E or SHBG were observed in response to bicalutamide therapy when given to women for the treatment of AR(+), ER/PR(−) MBC. These circulating hormones require further evaluation for use as a pharmacodynamic marker.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-02.
Abstract PD07-05: A randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer
Authors: Hasegawa Y , Kohno N , Horiguchi J , Miura D , Ishikawa T , Hayashi M , Takao S , Kim SJ , Tanino H , Miyashita M , Konishi M , Shigeoka Y , Yamagami K , Akazawa K
Published: August 2014

Background: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate, and it induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. ZOL has also been found to have antitumor effects that include an angiogenesis inhibiting action, an inhibitory effect on tumor cell adhesion to bone, an inhibitory effect on invasion of the extracellular matrix, and activation of a gdT cells. In addition, it has been found to have a synergistic anti-proliferative effect when used in combination with antitumor drugs.

In this study we investigated the pathological complete response (pCR) rate when ZOL is added to anthracycline followed by taxane to treat T2 and T3 breast cancer patients as a neoadjuvant chemotherapy.

Methods: Women with resectable invasive StageIIA-IIIB (T ≥3 cm or T ≥2 cm and lymph node positive) breast cancer who are HER-2-negative, between 20 and 70 years of age, and ECOG PS 0–1 were eligible.

Patients with distant metastasis, patients who have had received chemotherapy, hormone therapy, or radiotherapy for breast cancer, patients with serious complications, such as heart disease or an infection, patients with a complicating dental or jaw infection or traumatic condition of the teeth, and patients with a history of treatment with a bisphosphonate within the previous 12 months were excluded.

A total of 4 courses of FEC100 were administered every 3 weeks followed by weekly paclitaxel for 12 courses. ZOL 4mg was administered every 3–4 weeks a total of 7 times.

Patients were randomized 1:1 to chemotherapy + ZOL group or chemotherapy alone group, according to the presence or absence of lymph node metastasis, estrogen receptor (ER) status, and their menopausal status.

The primary endpoint was the rate of pCR defined as absence of invasive disease in the breast at surgery. Secondary endpoints were tumor response rate (RECIST ver1.0), the breast-conserving surgery ratio, and disease-free survival (DFS).

We calculated the sample size on the basis of a pCR rate of 18% in the chemotherapy alone group and 35% in the chemotherapy + ZOL group, at 5% significance level based on the one-sided chi-square test with the statistical power of 80%, and as a result we targeted a patient sample size of 180 patients.

Results: 188 patients were recruited between March 2010 and April 2012. Results of the primary analysis of efficacy and safety will be presented.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-05.
Abstract PD07-08: Zoledronic acid specifically inhibits development of bone metastases in the post-menopausal setting – evidence from an in vivo breast cancer model
Authors: Holen I , Wang N , Reeves KJ , Fowles AM , Croucher PI , Eaton CL , Ottewell PD
Published: August 2014

Background: A number of recent clinical trials have suggested that the benefits of adjuvant bone targeted treatments on risks of recurrence or death in early breast cancer are restricted to women with established menopause. We have used a model system that mimics pre- and post-menopausal status to investigate the effects of zoledronic acid on breast tumour growth in bone, demonstrating a differential anti-tumour effect in these two settings.

Methodology: Tumour growth was assessed by in vivo imaging following intra-cardiac inoculation of luciferase expressing MDA-MB-231 breast cancer cells in 12-week old female Balb-c nude mice. Animals underwent ovariectomy (OVX, mimicking the post-menopausal setting) or a sham operation (mimicking the pre-menopausal setting) 7 days after tumour cell implantation (n = 10/group). In treatment experiments, OVX and sham operated animals received either saline or 100ug/kg zoledronic acid (ZOL) weekly s.c. from day 4. Effects on bone were assessed by uCT analysis, bone histomorphometry and measurement of serum bone markers. Presence of tumour cells in bone was detected by multiphoton microscopy.

Results: OVX induced significant bone loss compared to sham within 2 weeks, which was completely inhibited by ZOL. Tumour growth was detected in the long bones of 29% of animals in the sham group on day 35 following tumour cell inoculation, and this was not affected by ZOL treatment. In contrast, 83% of the OVX animals had detectable tumours in the long bones, demonstrating that OVX mediated changes to the bone microenvironment that stimulated tumour growth. Crucially, this OVX-induced increase in tumour growth was completely prevented by weekly ZOL treatment, with only 17% of animals in the OVX+ZOL group having detectable bone tumours compared to 83% in the OVX+saline group. Multiphoton microscopy revealed that numerous individual tumour cells were present in long bones of animals in the OVX+ZOL group, supporting that ZOL acts by inhibiting an OVX-mediated trigger of tumour cell proliferation.

Conclusions: Our data are in agreement with those reported from clinical trials of adjuvant zoledronic acid, showing an anti-cancer effect exclusively in the post-menopausal setting. This is the first demonstration that zoledronic acid prevents tumour progression in bone specifically through inhibition of OVX-induced proliferation of tumour cells resident in the bone marrow.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-08.
Abstract S2-2: Sentinel Lymph Node Biopsy Before or After Neoadjuvant Chemotherapy - Final Results from the Prospective German, multiinstitutional SENTINA-Trial -
Authors: Kuehn T , Bauerfeind IGP , Fehm T , Fleige B , Helms G , Lebeau A , Liedtke C , von Minckwitz G , Nekljudova V , Schrenk P , Staebler A , Untch M
Published: August 2014

Background: The optimal timing for sentinel lymph node biopsy (SLNB) in the neoadjuvant setting is still unclear. Evidence for both, feasibility (detection rate, DR) and accuracy (false negative rate, FNR) of SLNB before and after primary systemic treatment (PST) is restricted to monocentric and/or retrospective trials. The success rates for SLNB are particularly unclear for patients who are downstaged from a cN1 to a ycN0 status.

Material and Methods: The German SENTINA (SENTInel NeoAdjuvant) trial is a 4-arm prospective multicenter cohort study designed to evaluate a specific algorithm for the timing of a standardized SLNB procedure in patients, who undergo PST and to provide reliable data for the DR and FNR in different settings. Patients were categorized into four treatment arms according to the clinical axillary staging before and after chemotherapy. Patients with a cN0 status underwent SLNB prior to PST and were categorized as arm A and B: If the SLN was histologically negative no further axillary surgery was performed after PST (arm A), whereas in case of histologically positive SLN status, a second SLNB and axillary dissection (AD) was performed after PST (arm B). Patients with a cN1 status prior to PST underwent no axillary surgery prior to PST and were stratified as arm C and D: If patients converted to cN0 after PST, SLNB and AD were performed (arm C); patients presenting with cN1 status after PST underwent classical AD (arm D).

Results: 1737 eligible patients from 103 institutions entered the trial. From these 662 patients were classified as arm A, 360 pts as arm B, 592 pts as arm C and 123 pts as arm D.

The DR for SLNB was 1013/1022 (99.1%) before PST (arms A and B), 474/592 (80.1%) in Arm C (after PST), and 219/360 (60.8%) in arm B (after prior SLNB and PST) (p < 0.001). 226/474 pts (47.7 %) in arm C with a detected SLN after PST had a positive and 248 (52.3 %) had a negative axillary status. The SLN was false negative in 32 pts (14.2 %, 95% CI 9.9%–19.4%). From 219 patients in arm B with a detected SLN after PST 64 (29.2 %) had a positive and 155 (70.8 %) a negative axillary status. The SLN was false negative in 33 pts (51.6 %, 95% CI 38.7%–64.2%).

Conclusion: In patients, who convert from a positive to a negative cN stage during PST the DR for the SLNB is significantly lower compared to patients, who undergo SLNB prior to any other treatment. The FNR is less favorable compared to primary SLNB. Prior systemic and/or surgical treatment significantly impairs the success rates of SLNB.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S2-2.
Abstract OT3-1-06: CIBOMA/2004-01_GEICAM/2003-11: A randomised phase III trial assessing adjuvant capecitabine (Cap) maintenance therapy after standard chemotherapy for triple-negative early breast cancer (EBC)
Authors: Barrios CE , Lluch A , Ruiz-Borrego M , Bines J , Torrecillas L , Carrasco E , Segalla JGM , Ruiz A , Garcia-Saenz JA , Torres R , De la Haba-Rodriguez J , Garcia-Martinez E , Morales S , Gomez H , Salvador-Bofill J , Hernando A , Martin M
Published: August 2014

Background: The ideal adjuvant treatment of triple negative EBC remains to be defined. CIBOMA/2004-01_GEICAM/2003-11 is a multinational randomized phase III trial exploring adjuvant Cap after the conclusion of conventional chemotherapy in triple-negative EBC patients.

Materials and Methods: Patients with operable, node-positive (or node-negative with tumour diameter ≥1 cm), hormone receptor-negative, HER2-negative EBC that have received 6–8 cycles of standard anthracycline and/or taxane-containing chemotherapy in the (neo)adjuvant setting (doxorubicin–cyclophosphamide x 4 allowed for node-negative disease), followed by radiotherapy (if indicated) are eligible. After central confirmation of triple negativity by immunohistochemistry, patients were randomised to either 8 cycles of Cap (1,000 mg/m2 bid, d1–14 q21d) or observation. Stratification factors: centre, prior taxane (yes vs. no), involved nodes (0 vs. 1–3 vs. ≥4) and phenotype (basal vs. non-basal). The primary endpoint is disease-free survival (DFS). Secondary endpoints include 5-year DFS, overall survival and safety. An optional pharmacogenetic sub-study will explore polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase in relation to efficacy and tolerability of Cap.

Present Status: Recruitment of 876 randomized patients was completed in September 2011. Statistical assumptions: expected 30% reduction in the risk of recurrence at 5 years (64.7% to 73.7%, HR 0.701), power of 80% and 0.05 two-sided significance level. Final efficacy analysis will be triggered by 255 events. Baseline characteristics are well balanced and shown in the table below. 75.0% of the patients completed the 8 cycles of adjuvant Cap.

Baseline patients characteristics Capecitabine (n = 448)Observation (n = 428)Median Age, years (range)51 (20-79)50 (24-83)Basal Phenotype,%70.772.2Histology,%  Ductal87.786.1Lobular1.82.3Other9.811.4Unknown0.70.2Grade,%  13.32.8218.119.0371.969.6Not determinable6.08.4Unknown0.70.2Chemotherapy received,%  Adjuvant (only)78.982.2Neoadjuvant (only)15.615.0Adjuvant + Neoadjuvant4.22.6Unknown1.30.2Postmenopausal,%69.267.3Prior Chemotherapy Agents,%  Anthracyclines without taxanes32.132.2Anthracyclines and taxanes67.267.6Unknown0.70.2

Conclusions: This randomized phase III adjuvant trial in triple negative EBC patients has completed accrual and event follow up is ongoing. The trial is sponsored by CIBOMA/GEICAM.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-06.
Abstract P1-02-04: Array based resolution of HER2 amplification status in breast carcinomas displaying apparent chromosome 17 aneusomy
Authors: Portier BP , Wang Z , Minca E , Lanigan C , Downs-Kelly E , Tubbs RR
Published: August 2014

Background:

Molecular inversion probe (MIP) arrays offer high-quality copy number and genotype data with whole-genome coverage and high resolution of cancer related genes. The MIP array assay is specifically designed for use with Formalin Fixed Paraffin Embedded (FFPE) tissue due to its design which utilizes hybridization of short sequence inversion probes. In this study, we performed MIP array analysis on a cohort of breast carcinomas with putative chromosome 17 aneusomy identified by HER2/CEP17 dual probe FISH. We hypothesized that MIP array performed on cases with chromosome 17 aneusomy would allow HER2 amplification status resolution and provide additional clinically actionable data on genes with predictive and prognostic significance.

Design:

DNA was extracted from formalin fixed paraffin embedded tissue (Qiagen,Valencia, CA) from invasive breast carcinomas following macrodisection. Breast carcinomas utilized in this study segregated into three groups: 1) Aneusomic 2) Monosomic, and 3) Eusomic cases as determined by FISH utilizing a centromere 17 reference probe (PathVysion; Abbott Molecular). Matched patient normal lymph nodes were performed for a subset of cases from each group. MIP-array data was collected using the Affymetrix OncoScan™ array (Affymetrix, Santa Clara, CA). Analysis of array data was performed using Nexus software v6 (BioDiscovery, Inc., Hawthorne, CA).

Result:

Array-based detection of HER2 amplification in aneusomic breast carcinomas showed 100% concordance with single probe (HER2) FISH. However, based on genomic profiling, these cases showed great variability in regions of aneusomy along chromosome 17. In our aneusomic cohort, one region of chromosome 17 showed conserved eusomy status. This region was utilized for both array and FISH based ratio to resolve HER2 amplification status in 18 of 22 (82%) of cases. In addition to HER2 status resolution by MIP array, gains and losses in genes involved in modulating therapy were also identified, using this single assay.

Conclusion:

Use of MIP array-based genotyping as a single reflex assay in breast carcinomas with apparent chromosome 17 aneusomy resulted in HER2 amplification status resolution. In addition, use of this assay in our aneusomic cohort resulted in identification of a highly conserved region of chromosome 17 that is highly resistant to gains or losses in ploidy. The “D17S122” region was confirmed by FISH and use of a HER2/D17S122 ratio, allowed resolution of HER2 amplification status. In addition to HER2 status resolution and copy number data, MIP Array also provided comprehensive genomic coverage for analysis of non EGFR family genes potentially important for prognosis and therapy response prediction.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-02-04.
Abstract P2-15-04: Trastuzumab re-treatment following adjuvant trastuzumab and the importance of distant disease-free interval: The HERA trial experience
Authors: Metzger Filho O , Procter M , de Azambuja E , Krieguer M , Gelber RD , Piccart M
Published: August 2014

Background: Trastuzumab (T) forms the backbone of the current first-line treatment of advanced HER2+ breast cancer. In the present study we sought to evaluate the impact of the time interval between the end of adjuvant trastuzumab and distant recurrence (TDRI), upon a) overall survival (OS), b) the duration of trastuzumab-based regimens (T) in the advanced setting.

Patients & Methods: a) The first hypothesis involved 187 pts on HERA treated with adjuvant T and diagnosed with distant recurrence after the scheduled treatment period of 1 year at 4 years median follow-up. The impact of TDRI on OS from distant recurrence was evaluated in a Cox model adjusted for tumor size, nodal and hormone receptor status at time of enrollment into the HERA trial. b) The second hypothesis involved 90 patients retreated with T in the metastatic setting. A questionnaire was sent to investigators retreating pts with T upon distant recurrence; 144 of 156 questionnaires were returned (93%), and 90 pts were selected based on available clinical information and consent for subsequent studies (14 pts were randomized to observation and received adjuvant trastuzumab after crossover).

Results: a) There was no statistically significant relationship between TDRI following 1yT and OS from distant recurrence: HR 0.99, p = 0.46; HR 0.99, p = 0.27 from the stratified and unadjusted Cox proportional hazard models, respectively. The median OS from distant recurrence was numerically longer among pts with a TDRI of ≥ 12 months (n = 103) than < 12 months (n = 84) but not statistically significant (23.7 vs. 17.8 months, p = 0.47). b) The median duration of T-based regimens for metastatic disease was 8.8 months (n = 88), 9.4 months in the ER+ cohort (n = 36) and 8.8 months in the ER- cohort (n = 52); (n = 2, missing). Sites of first distant recurrence and subsequent disease progression for the 90 pts were hierarchically distributed as below.

 First distant recurrence n (%)Subsequent progression n (%)CNS6 (6.7%)22 (24.4%)Visceral45 (50.0%)39 (43.3%)Skeletal25 (27.8%)9 (10.0%)Soft Tissue14 (15.6%)9 (10.0%)No event-11 (12.2%)

Conclusions: In the HERA trial, TDRI following 1yT did not impact on OS from distant recurrence in pts experiencing distant disease recurrence. This may be due to the benefit of anti-HER2 regimens in subsequent lines of therapy. Although our sample size is limited, the present analysis suggests that pts experiencing a shorter interval (≤ 12 months) from the end of adjuvant trastuzumab to distant recurrence derive similar benefit from trastuzumab-containing regimens in the metastatic setting when compared to the cohort with an interval > 12 months. CNS relapse in HER2-postive breast cancer remains a clinical problem.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-15-04.
Abstract P3-12-06: Statin use and outcome among breast cancer patients treated with neoadjuvant systemic chemotherapy
Authors: Chavez-Mac Gregor M , Lei X , Litton JK , Melhem-Bertrand A , Giordano SH , Masuda H , Ueno N , Gabriel HN , Valero V
Published: August 2014

BACKGROUND: Statins are cholesterol-reducing agents that affect intracellular pathways associated with tumorigenesis and inflammation. Preclinical studies have demonstrated that statins have anti-tumor effects and epidemiological studies have suggested that the use of HMG-CoA-reductase inhibitors is associated with improved long-term outcomes among breast cancer patients. In this study we sought to evaluate the effect of statins in the pathologic complete response (pCR) and survival outcomes among breast cancer patients receiving neoadjuvant systemic chemotherapy (NST).

METHODS: Retrospective study including patients diagnosed between 1995-2007 with invasive primary breast cancer. All patients received neoadjuvant systemic chemotherapy. Use of statins during NST was identified by review of medical records. We compared pCR rate, relapse-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) between statin-users and non-users. pCR was defined as no evidence of invasive carcinoma in the breast and axillary lymph nodes at the time of surgery. Descriptive statistics and Cox proportional hazards model were used in the analyses.

RESULTS: From the 1449 patients included, 74 (5.11%) were treated with statin during NST. Statin users were more likely to be older, overweight/obese and more likely to be also treated with beta-blockers or metformin. No differences in pCR were observed according to statin use (16.2% vs 17.6% p = 0.75). In the multivariable model, the use of statin was not an independent predictor of pCR. With 55 months of follow-up (415 recurrences and 359 deaths), the 5-year RFS was 82% in the statin-treated patients and 70% in the non-statin treated group (p = 0.03), no differences were seen in DSS or OS. Subset analyses according to tumor subtype demonstrated patients with hormone receptor-positive tumors treated with statins had better 5-year RFS (93% vs 76%; p = 0.01). In the multivariable model, no association was observed between statin use and outcome.

CONCLUSIONS: In our cohort of patients, statin use during NST was not independently associated with pCR, RFS, DSS and OS. Further studies with larger number of statin-treated patients are warranted to clarify the role of HMG-CoA reductase inhibitors in the treatment of breast cancer patients. In addition future studies should evaluate the effect of prolonged statin use and take the different type of statin subtype into account.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-12-06.
Abstract PD1-3: Ph1b study of the PI3K inhibitor GDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer
Authors: Juric D , Saura C , Cervantes A , Kurkjian C , Patel MR , Sachdev J , Mayer I , Krop IE , Oliveira M , Sanabria S , Cheeti S , Lin RS , Graham RA , Wilson TR , Parmar H , Hsu JY , Von Hoff DD , Baselga J
Published: August 2014

Background: GDC-0032 is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant cancers. GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that GDC-0032 has enhanced activity against PI3K alpha isoform (PIK3CA) mutant breast cancer cell lines. Preclinical data also show enhanced antitumor activity when GDC-0032 is combined with fulvestrant.

Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of GDC-0032 doses ranging from 6-9 mg QD in combination with fulvestrant 500mg q4wk (with loading dose of 500mg at day 1, 14 and 28) in a modified 3+3 design. A dose expansion cohort was conducted at the recommended Phase 2 dose of 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment of PI3K pathway inhibition by paired tumor biopsies and by FDG-PET, and anti-tumor activity by RECIST.

Results: As of 1 Mar 2013, 17 patients were enrolled onto this study with the completion of dose escalation. No dose limiting toxicities (DLTs) were observed at either the 6 mg or 9 mg dose levels. Adverse events (AEs) assessed by the investigator as related to GDC-0032 in ≥10% of patients, were diarrhea, hyperglycemia, stomatitis, fatigue, asthenia, decreased appetite, nausea, mucosal inflammation and rash. No observed apparent PK interactions were observed between GDC-0032 and fulvestrant. The median number of prior systemic therapies was 6. Metabolic partial responses via FDG-PET (≥ 20% decrease in mSUVmax) were observed in 8 out of 11 patients assessed (73%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg GDC-0032 dose levels. These include patients who have had prior treatment with fulvestrant. As of 29 May 2013, enrollment onto the dose escalation and expansion cohort has been completed (n = 27). Updated data on safety, pharmacodynamics, efficacy, and biomarker correlates will be presented.

Conclusions: The combination of GDC-0032 and fulvestrant is a well-tolerated regimen with promising preliminary efficacy. GDC-0032 is being further investigated in combination with fulvestrant for patients with hormone receptor-positive advanced breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-3.
Abstract PD3-3: Next generation sequencing shows clonal selection after treatment with anastrozole or fulvestrant in a randomized trial of postmenopausal patients with large operable or locally-advanced hormone-receptor-positive breast cancer
Authors: Iggo RD , Wood HM , Rabbitts P , Quenel-Tueux N , Mauriac L , MacGrogan G , Bonnefoi H ,   HORGEN Investigators
Published: August 2014

Background: Unlike chemotherapy, endocrine therapy is not clastogenic or mutagenic, so genetic changes arising during treatment are unlikely to be secondary events provoked by iatrogenic DNA damage. Endocrine therapy for breast cancer is thus a clean setting in which to explore the evolution of tumour genomes under treatment, and the changes seen are likely to be biologically meaningful. To identify such changes we have analysed pre and post treatment biopsies from a clinical trial that compared two endocrine therapies.

Patients and methods: DNA was extracted from pre and post treatment samples from 20 patients enrolled in the HORGEN trial. Postmenopausal patients with large operable or locally-advanced hormone-receptor-positive breast cancer were randomly assigned to receive either neoadjuvant anastrozole or fulvestrant for 6 months in this multicenter randomized phase II study. Low depth next generation sequencing was used to generate DNA copy number profiles for each sample.

Results: The copy number profiles were similar before and after treatment in 10 cases. In three cases new amplicons appeared. In one case the amplicon contained the ESR1 gene, in another the FOXA1 gene, and in the third the NCOA3 gene. In the remaining seven cases where the profiles changed after treatment, the differences affected whole chromosomal arms. In six of these cases the profiles became simpler, indicating that clones with gains and losses of chromosomal arms had been counterselected by the treatment.

Conclusions: Differences between the pre and post treatment biopsies were surprisingly frequent and informative. Genes directly implicated in estrogen signalling were amplified in three cases. This suggests that specific amplicons confer resistance to endocrine therapy. From a clinical perspective, their appearance in a post treatment biopsy probably indicates that the treatment should be changed. A possible explanation for the chromosomal arm changes after treatment, a phenomenon we have dubbed the “wandering arms” phenotype, is that endocrine therapy deprives tumour cells of signals that are necessary for the survival of clones with copy number changes affecting whole chromosomal arms.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-3.
Abstract S1-01: The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study (BIG 1-06)
Authors: Piccart-Gebhart M , Holmes AP , de Azambuja E , Di Cosimo S , Swaby R , Untch M , Jackisch C , Lang I , Smith I , Boyle F , Xu B , Barrios C , Gelber R , Eidtmann H , Baselga J
Published: August 2014

Background: The NeoALTTO study demonstrated a significantly higher breast pathological complete response (pCR) rate (NSABP definition – ypT0/is) with dual HER2 blockade using lapatinib and trastuzumab compared with single HER2 blockade using either lapatinib or trastuzumab (51.3% vs. 24.7% vs. 29.5%, respectively; p< 0.01 for both) in HER2 positive primary breast cancer (BC). A similar pattern was seen for locoregional pCR (ypT0/is ypN0) (Baselga J et al. Lancet 2012).

Material and Methods: From January, 2008, to December, 2009, 455 patients were randomized from 99 participating sites in 23 countries. Patients were randomized to receive either lapatinib 1500 mg/d (154 pts), or trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly (149 pts), or lapatinib 1000 mg/d with trastuzumab for a total of 6 weeks (152 pts). After this biological window, patients continued on the same targeted therapy plus weekly paclitaxel 80 mg/m2 for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). After surgery, patients received 3 cycles of adjuvant FEC followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy), with on-going follow-up planned until 10 years after last randomised patient.

Secondary objectives included disease-free survival and overall survival (OS). Following current practice and draft FDA recommendations for neoadjuvant trial endpoints, an amendment was made to the protocol secondary objectives (released in May 2013). DFS (from surgery) was replaced by event-free survival (EFS) from randomisation; OS from surgery was correspondingly replaced with OS from randomisation, and examination of the association between these survival endpoints and locoregional pCR (ypT0/is ypN0) was added as a secondary objective. EFS was defined as the time from randomization to first EFS event (breast cancer relapse, second primary malignancy or death without recurrence). OS was defined as the time from randomization to death from any cause.

Results: The clinical cut-off date for the first planned analysis of these secondary objectives was on 26 May 2013, three years after the date of last surgery. Data cleaning is ongoing and analysis will be completed by November 2013. Results for EFS, OS and their association with pCR will be presented at the meeting.

Funding: GlaxoSmithKline is the sponsor of this trial.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-01.
Abstract B08: Triptolide has antitumor effects in lung cancer via Wnt pathway inhibition.
Authors: Li Youqiang , Zheng Li , Shen Binghui , Kim Jae , Raz Dan
Published: August 2014

Introduction: Triptolide is an extract of the herb Tripterygium wilfordii (Tw), which has been used to treat autoimmune disorders in traditional Chinese medicine. It has also been reported to have anti-cancer effects in vitro, although little is known about its mechanism of action. The Wnt/B-catenin pathway has been implicated in regulating cancer stem cells in lung cancer, making this pathway a potential target for novel lung cancer therapies.

Methods: Here we tested the efficacy of triptolide in several lung cancer cell lines. We elucidated a Wnt pathway mechanism for triptolide effect in lung cancer, first by using a Wnt focused cDNA array in vitro. We examined the effect of triptolide on tumor cell death using flow cytomotery and a beta-galactosidase assay. We tested the ability of triptolide to prevent development of lung tumors in the E160D transgenic mouse model of lung cancer, which carries a somatic mutation in the DNA repair enzyme flap endonuclease-1 (FEN-1). Twelve month old mice were fed triptolide 1mg/kg daily for 2 months and were sacrificed at 18 months along with a control group.

Results: Triptolide had more potent therapeutic efficacy in multiple lung cancer cell lines compared with cisplatin and paclitaxel, in vitro. In H460 and A549 cell lines, we found that triptolide resulted in Wnt pathway silencing via overexpression of Wnt inhibitory factor-1 (WIF-1), which occurs due to promoter demethylation. Addition of recombinant Wnt3a, which causes Wnt pathway activation, partially rescues the effect of triptolide on lung cancer cell lines. Triptolide resulted in cellular senescence as demonstrated by beta-galactosidase assay. Finally, in the E160D transgenic mouse model of lung cancer, a two month course of oral triptolide treatment decreased the development of lung tumors from 70% to 30% at 18 months (p=0.01). There were no observed clinical toxicities at the dosage of triptolide used.

Conclusions: Triptolide has potent anti-cancer effects in vitro in lung cancer cell lines, and significantly decreases lung tumor development in a transgenic mouse model. Triptolide suppresses the Wnt pathway by causing upregulation of WIF-1a by promoter demethylation. Future studies are needed to test this promising and novel Wnt-targeting therapy in lung cancer animal models, and to identify biomarkers which may predict sensitivity in particular subgroups of lung cancer patients.

Citation Format: Youqiang Li, Li Zheng, Binghui Shen, Jae Kim, Dan Raz. Triptolide has antitumor effects in lung cancer via Wnt pathway inhibition. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B08.