bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract OT1-1-03: A phase 3 randomized, double-blind trial comparing PF-05280014 + paclitaxel vs. trastuzumab + paclitaxel for treatment of HER2+ metastatic breast cancer patients
Authors: Ewesuedo R , Barker KB , Taylor CT , Jacobs I
Published: August 2014

Background: PF05280014 is being developed as a potential biosimilar to trastuzumab. PF-05280014 demonstrated similarity to trastuzumab in nonclinical evaluations. In a Phase I trial in healthy volunteers, PF-05280014 pharmacokinetic characteristics and safety profile were shown to be similar to those of trastuzumab. The goal of this Phase 3 trial is to demonstrate that the efficacy and safety of PF-05280014 + paclitaxel are similar to those of trastuzumab sourced from the EU (trastuzumab-EU) + paclitaxel in women with HER2-positive metastatic breast cancer.

Trial design: In this randomized, double-blind trial, patients will be randomized 1:1 into 2 arms: PF-05280014 + paclitaxel and trastuzumab-EU + paclitaxel. Randomization will be stratified by prior adjuvant trastuzumab exposure and estrogen receptor status. The order of infusion will be PF-05280014 or trastuzumab (4 mg/kg in Cycle 1; 2 mg/kg thereafter over 90 min) first followed by paclitaxel (80 mg/m2).

Eligibility: Female patients, aged ≥18 y with confirmed HER-2 overexpressing metastatic breast cancer, ≥1measurable lesion (RECIST), Eastern Cooperative Oncology Group status 0–2, normal left ventricular ejection fraction, and normal laboratory values are eligible. Key exclusion criteria are prior systemic therapy for metastatic disease, prior cumulative dose of anthracyclines >400 mg/m2, and major surgery, radiotherapy or investigational agents within 4 weeks. All subjects must provide informed consent.

Aims: The primary objective is to demonstrate the similarity in objective response rate (ORR) of PF-05280014 + paclitaxel treatment to that of trastuzumab-EU + paclitaxel. Secondary objectives include evaluating 1-year progression-free survival, safety, pharmacokinetics, and immunogenicity of these combination treatments.

Statistical methods: This study tests whether the ORR of PF-05280014 is similar to that of trastuzumab-EU, using a margin of 13%, i.e., 5% alpha for non-inferiority. Assuming 60% ORR in both arms, 600 patients (300/arm) will be needed to achieve 90% power. Assuming 10% attrition, a total of 660 patients will be randomized. The intent-to-treat (ITT) population is defined as all subjects who are randomized to receive treatment. The per-protocol population is defined as all subjects who are randomized to and receive treatment and do not have any major protocol violations and will be used for evaluation efficacy endpoints.

Accrual: The target accrual of this global trial is 660 patients.

Contact information: For further information, please contact the Director, Clinical Trials Disclosure Group, Pfizer Inc. (marla.brickman@pfizer.com).

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-03.
Abstract OT2-6-13: A randomized phase 2 study of the triplet combination of ridaforolimus (RIDA), dalotuzumab (DALO) and exemestane (EX) compared to the ridaforolimus, exemestane doublet in high proliferation, estrogen receptor positive (ER+) advanced breast cancer
Authors: Rugo HS , Tredan O , Ro J , Morales SM , Musolina A , Afonso N , Ferreira M , Park KH , Cortes J , Tan AR , Blum JL , Eaton L , Mauro D , Gause C , Im E , Baselga J
Published: August 2014

Background: The clinical benefit of combination of mTOR inhibition and anti-hormonal therapy has been previously established and represents a new standard of care for patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Preclinical evaluation of the mTOR pathway demonstrates that dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A completed phase 1 study of the combination of the mTOR inhibitor, RIDA and the anti-IGFR antibody, DALO demonstrated preliminary signals of anti-tumor activity. This was further evaluated in a recently completed phase 2 study of RIDA-DALO compared to exemestane in ER+ ABC. Final safety and efficacy results from that phase 2 study will be reported at this meeting (see Baselga et al). Building upon the clinical synergies of mTOR and EX as well as the biologic relationship of the mTOR and IGFR pathways, a clinical study has been initiated to evaluate the triplet combination of RIDA-DALO-EX compared to RIDA-EX. Methods: This is a multicenter, international, randomized phase 2 study of the triplet combination of RIDA (10 mg by mouth daily for 5 out of every 7 days), DALO (10 mg/kg IV weekly), and EX (25 mg QD) compared to RIDA (30 mg by mouth daily for 5 out of every 7 days) and EX (25 mg QD) in high KI67 (≥15%) expressing ER+, ABC. Approximately 84 patients will be randomized 1:1 to either triplet or doublet therapy. Key eligibility criteria include: HR+ and HER-2 negative measurable ABC, prior therapy with a non-steroidal aromatase inhibitor, and KI67 labeling index ≥15%. The primary endpoint of the study is progression free survival (PFS). Key secondary endpoints include evaluation of percent (%) reduction from baseline in the sum of imaging measurements (target lesion diameters or volumes) at 16 weeks between the two arms, and overall response rates. The sample size is event driven with a target of 38 PFS events, which provides approximately 80% power, at 1-sided alpha of 0.1, to detect a HR of 0.5, corresponding to an approximate 100% improvement in median PFS, from 10.6 to 21.2 months. Safety parameters or adverse experiences of special interest include hyperglycemia, stomatitis, mucosal inflammation, pneumonitis and hearing loss. Accrual has been completed with results expected in May 2014.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-13.
Abstract OT2-6-15: Efficacy and safety of vintafolide alone and vintafolide plus paclitaxel vs paclitaxel alone in advanced triple negative breast cancer subjects using etarfolatide subject selection
Authors: Schmidt EV , Leighton-Swayze AM , Hanson ME , Brown H , Gause CK , El Galta R , Denker AE , Yao S-L
Published: August 2014

Background: Vintafolide (V) is a folic acid-vinca alkaloid small molecule drug conjugate that targets tumors that over-express the folate receptor (FR). 99mTc-etarfolatide (EC20) is a folate-targeted molecular imaging agent being developed to identify FR-positive tumors. Data suggest that triple negative breast cancers (TNBCs) expressing high levels of FR are likely to benefit from treatment with vintafolide.

Trial design/Patient eligibility: This is a multicenter, randomized, open-label, Phase IIa trial in subjects with advanced TNBC. Patients will be evaluated for tumor specific expression of the FR using a EC20 SPECT/CT scan and classified as FR(100%) if 100% of RECIST 1.1 target lesions are FR-positive. Only FR(100%) patients are eligible for treatment and will be randomized in a 1:1:1 ratio to V alone, V + paclitaxel (P) or P alone. V will be administered at 2.5 mg IV 3x/week for 2 weeks on Days 1, 3, 5, 15, 17 and 19 of a 28-day cycle. P will be administered at 80 mg/m2 IV on Days 1, 8, 15, and 22.

Specific aims: The primary endpoint for the trial is centrally assessed progression free survival (PFS). Secondary objectives include: assess the frequency of target tumors expressing FR(100%) vs FR(20-80%) vs FR(0%) in subjects with TNBC using EC20 SPECT scans; compare the clinical activity in subjects with advanced TNBC of V alone vs P and V + P vs P alone as measured by objective response rate (ORR), (complete response [CR] + partial response [PR]), clinical benefit rate (CBR; CR + PR + stable disease for ≥6 months), and overall survival; and assess the safety and tolerability of V alone vs P alone and V + P vs P alone in subjects with advanced TNBC.

Statistical methods and target accrual: PFS and overall survival will be assessed in the intention to treat population using a stratified Cox model with Efron's tie handling method, and Kaplan-Meier method for PFS and OS curve estimation, respectively, in each treatment group.

Inferential comparisons between the arms will be tested using the stratified log-rank test at one sided alpha level of 5%. This study will randomize 34 subjects into each treatment group with total study duration of ∼16-17 months. The study has 80% power to demonstrate that either patients treated with V or patients treated with V + P combination have a higher median time to an event of PFS than subjects treated with P at an unadjusted one-sided, 5% alpha-level, if the underlying constant hazard ratio between treatment groups is 0.5 and median survival time of 2.6 months. First patient enrollment is targeted for October.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-15.
Abstract P1-08-15: Prognostic value of five different histologic scoring systems for tumor regression after neoadjuvant chemotherapy of breast cancer in luminal type breast cancer
Authors: Sinn P , Elsawaf Z , Kaip G , Heil J , Aulmann S , Marmé F , Schneeweiss A
Published: August 2014

Background: Complete pathologic tumor regression (pCR) and molecular tumor characteristics are the major determinants for the outcome of patients undergoing neoadjuvant chemotherapy. Recently, we have raised the question, if complete pathologic tumor regression (pCR) is a reliable endpoint in cohorts with an abundance of luminal subtypes (Marmé et al., Int J Cancer 2013). Therefore, we have compared the prognostic value of different histologic scoring systems for the evaluation of partial tumor regression in luminal type breast cancer in this study.

Methods: We retrospectivly reviewed tumor resection specimens of the GEDOC/GEsDOC (Schneeweiss et al., Eur J Cancer 2004) and H3E-MC-S080 (Schneeweiss et al., Ann Oncol 2010) clinical trials. Histologic tumor regression was scored according to five different regression scoring systems (Sataloff, Miller-Payne, RCB score, Sinn, and NSABP). Molecular subtypes were classified according to established immunohistologic definitions of intrinsic subtypes.

Results: A total of 152 luminal type breast cancers were available for histologic evaluation (139 with HER2 negative and 13 with HER2 positive phenotype). Median follow-up was 63 months (9-105). pCR was observed in 10 patients according to the NSABP criteria. Overall survival was significantly better for patients with complete or near complete response (RCB class 0, 1) compared to moderate or extensive residual disease (RCB class 2, 3) with 5-y OAS of 97.6%+/- 1.6% vs. 81.7%+/-6.7% (p<0.001). Tumor response in lymph nodes (Sataloff lymph node score) was of similar prognostic value with 5-y OAS of 96.6%+/-2.3% (NA and NB responses) vs. 84.1%+/-5.6% (NC and ND responses, p<0.005). However, scores based on tumor cellularity (Miller-Payne or Sataloff tumor score) could not reliably identify prognostic subgroups. The Sataloff ND category of patients with viable lymph node metastasis and no therapeutic effect identified the worst outcome group (5-y OAS 69.2%+/-20.7%). In multivariate analyses only the RCB score and the HER2 status remained predictive parameters for survival (both p<0.05).

Conclusions: In luminal type breast cancers, the use of regression scoring systems that include the lymph node status (RCB score and Sataloff LN score) was superior to scoring systems which are based solely on tumor cellularity such as the Miller-Payne system. The HER2 status was of independent significance.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-15.
Abstract P1-08-32: Endothelin-1 genetic polymorphism as predictive marker for bevacizumab in metastatic breast cancer
Authors: Gampenrieder SP , Hufnagl C , Brechelmacher S , Huemer F , Hackl H , Rinnerthaler G , Romeder F , Muß C , Pircher M , Ressler S , Kronberger C , Mlineritsch B , Greil R
Published: August 2014

Background: Biomarkers predicting response or toxicity of bevacizumab containing therapy in breast cancer are of urgent need. The genetic variability of VEGF, its receptor or other genes involved in angiogenesis could explain the inter-patient variability of drug effects and treatment resistance.

Patients and methods: DNA was extracted from 180 paraffin-embedded tumor tissue blocks of patients with locally advanced or metastatic breast cancer treated with bevacizumab in combination with chemotherapy at our institution. We assessed the correlation of 11 SNPs in VEGF-A, VEGFR-1, STK39, endothelin-1 and uromodulin with outcome and toxicity.

Results: Only one SNP in endothelin-1 (rs5370 TT) was significantly associated with worse median progression-free survival (HR 2.13, 95% CI 1.04 to 4.35, P = .038) and median overall survival (HR 2.88, 95% CI 1.40 to 5.93, P = .0042) compared with the alternate genotypes combined. One VEGF genotype (VEGF-634 GG) was associated with a significantly higher rate of treatment-induced hypertension when compared with the alternate genotypes combined (P = .048).

Conclusion: Although these data need to be confirmed in larger trials, germline polymorphisms could help identifying patients who do not gain any benefit from anti-VEGF agents or who are at high risk of toxicity.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-32.
Abstract P1-13-11: Supervising circulating tumor cells during and beyond maintenance therapy with SERM or aromatase inhibitors. A way to better support our patients to make decisions in long-term survivorship
Authors: Pachmann K , Rabenstein C , Camara O , Ingo RB , Ulrich P
Published: August 2014

Background: Although current guidelines still support 5 years of hormone blocking therapy after primary breast cancer due to earlier results showing no benefit of longer treatment, recent data have shown that longer treatment with tamoxifen can better reduce recurrence and death. However, side effects with this therapy can be considerable and compliance declines with time. We, here, report data on monitoring circulating epithelial tumor cells (CETC) beyond maintenance therapy showing that even if maintenance therapy with SERM or aromatase inhibitors had been effective in reducing tumor cells in blood, there can be a reincrease after the end of maintenance therapy and that this is highly correlated with relapse.

Materials and methods: 7.5ml of anti-coagulated blood was drawn before the start of chemotherapy, after each cycle and after the end of chemotherapy. Using a nondissipative approach with only red blood cell lysis the white blood cells including the tumor cells were stained with a fluorescent labelled anti-epithelial antibody, positive events counted using an automated image analysis microscope and calculated per volume blood.

Results: 96 patients with nonmetastatic breat cancer were observed beyond maintenance treatment with hormone blocking therapy. Results on CETC were evaluable from 35 patients even after completion of therapy. Increasing cell numbers after the end of therapy were able to predict relapsing from long term relapse free survivors (p = 0.0001).

Conclusion: In breast cancer, a debate has been reiinitated with respect to the length of maintenane treatment. Even if hormone blocking maintenance treament is capable of reducing or even eliminating tumor cells circulating in peripheral blood and this is related to improved relapse free survival there may remain tumor cells in the body capable of regrowing and leading to late relapse. Monitoring of CETC in peripheral blood even after completion of maintenace therapy can early predict imminent relapse and help to decide whether to reinitiate hormone blocking therapy.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-11.
Abstract P1-13-12: Intermittent letrozole as adjuvant treatment in postmenopausal hormone-receptor positive early breast cancer patients
Authors: Balduzzi A , Bagnardi V , Volpe S , Cancello G , Iorfida M , Dellapasqua S , Sandri M , Goldhirsch A , Colleoni M
Published: August 2014

Background: Low-dose estrogen might induce apoptosis in breast cancer cells that develop resistance to antihormonal therapy. Letrozole withdrawal for 3-month might permit estrogenic stimulation in residual resistant disease susceptible to letrozole reintroduction. We investigated the impact of a 3-month letrozole free interval on serum Estradiol levels in patients with early stage breast cancer.

Patients and methods: Postmenopausal women with ER and/or PgR ≥ 10% of the cells, node-negative early breast cancer were eligible. Patients (pts) received letrozole (2.5 mg daily) for five years with a 3-month treatment free interval after the 1st year of therapy. The primary endpoint was to evaluate the increase in serum estradiol absolute levels after 3-month treatment free interval. The secondary endpoints were the evaluation of others biological markers (e.g. FSH, LH, Cholesterol, HDL, triglycerides, osteocalcin). Estradiol levels were quantified by ECLIA assay that measured estradiol concentrations with a 5 pg/ml lower detection limit. FSH and LH levels (mU/ml) were measured by ECLIA assay, Osteocalcin (ng/ml) by RIA assay, Cholesterol, HDL, and Triglycerides (mg/ml) by colorimetric assay.

Results: From November 2007 to February 2012, 130 evaluable pts were enrolled. The median age was 61 years. One-hundred ten pts (85%) had pT1 tumor, 88 pts (68%) presented grade 2 and 83 pts (64%) showed a Ki-67 LI <20%. Mean values of estradiol levels at time of discontinuation were 5.6 pg/ml (standard deviation: 1.7). Estradiol levels increased after a 3-month free interval by a mean of 3.3 pg/ml (66%; P <0.0001). FSH and LH levels decreased from baseline by a mean of 7.5 mU/ml (P<0.0001), and 1.4 mU/ml (P = 0.0062) respectively. Triglycerides decreased from baseline by a mean of 8.6 mg/dl (P = 0.036), and osteocalcin increased by a mean of 2.8 ng/ml (P = 0.013).

Conclusions: Intermittent Letrozole significantly impact on estradiol levels. This study provides further evidence supporting the role of intermittent letrozole in the adjuvant treatment of postmenopausal patients with endocrine responsive breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-12.
Abstract P2-01-04: High-density lipoprotein cholesterol is associated with mammographic density in premenopausal women
Authors: Flote VG , Frydenberg H , Ursin G , Wilsgaard T , Iversen A , Ellison PT , Wist EA , Egeland T , Thune I , Furberg A-S
Published: August 2014

Background: High-Density Lipoprotein Cholesterol (HDL-C), and ovarian steroid hormones and mammographic density have independently been associated with breast cancer development. However, little is known regarding the association between HDL-C, ovarian hormones and mammographic density in premenopausal women. Material and Methods: We assessed fasting HDL-C among 202 healthy women, aged 25-35 years, participating in the Energy Balance and Breast cancer Aspects (EBBA) study-I. Progesterone and estrogen were assessed both in serum (three times) and daily saliva across an entire menstrual cycle. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms taken at days 7-12 of the menstrual cycle during a narrow time frame, thereby avoiding potential bias due to variations in mammographic density during the menstrual cycle. The association between HDL-C, in combination with progesterone or estrogen and absolute mammographic density were studied in multivariable linear and logistic regression models, and potential confounding factors and effect modifiers were tested. Results: The participating women had a mean age of 30.7, mean HDL-C of 1.54 mmol/l, and absolute breast density of 34.7 cm2 (median 32.4 cm2). Among women in the lowest tertile of HDL-C (≤1.38mmol/l), we observed a positive association between midmenstrual salivary 17β-estradiol and absolute breast density (p = 0.014), and between luteal salivary progesterone and absolute breast density (p = 0.029). Among these women in the lowest tertile of HDL-C, we also observed that high 17β-estradiol throughout the menstrual cycle was associated with higher absolute mammographic density (above median absolute density, >32.4 cm2). Odds Ratio (OR) per standard deviation (SD) increase in salivary midmenstrual 17β-estradiol was 2.49 (95% confidence interval [CI] 1.12-5.53) for having a higher absolute mammographic density (>32.4 cm2). These associations between HDL-C, ovarian steroids and absolute mammographic density were not observed in the middle or highest tertiles of HDL-C. Conclusion: Our findings suggest that low HDL-C, a marker of dyslipidemia, in combination with high levels of either progesterone or estradiol may be associated with higher absolute mammographic density in premenopausal women.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-01-04.
Abstract P2-09-19: Zerumbone suppresses IL-1b-induced cell migration and invasion through inhibition of IL-8 expression and MMP3 expression in human triple negative breast cancer cells
Authors: Bae SY , Han JH , Kim S , Lee SK , Lee JH , Lee HC , Kim M , Kim J , Kil WH , Kim SW , Lee JE , Nam SJ
Published: August 2014

Background: Inflammation is a key regulatory process in breast cancer progression and severity. Several studies have demonstrated that prolonged exposure of breast tumor cells to inflammatory cytokines leads to epithelial-mesenchymal transitions (EMT), which is the principle mechanism involved in metastasis and tumor invasion. Disruption of the signaling pathways involved in EMT may therefore provide an effective treatment strategy for currently difficult to treat or untreatable cancers such as TNBC. The interleukin (IL)-1 plays a pivotal role on breast cancer proliferation, invasion and/or inflammation. Here, we investigated the correlation of MMP-3 and IL-8 on IL-1b-induced cell migration and invasion as well as the inhibitory effect of zerumbone on IL-1β-induced MMP-3 and IL-8.

Methods: Triple negative breast cancer cells (Hs578T and MDA-MB231) were cultured DMEM with 10% FBS and 1% antibiotics. The levels of IL-8 and MMP-3 mRNA were analyzed by real-time PCR. The levels of secreted IL-8 and MMP-3 protein expression were analyzed by ELISA and western blot analysis, respectively. Cell viabilities by drug were analyzed by MTT assay. Cell invasion and migration was detected by Boyden chamber assay.

Results: The level of IL-8 and MMP-3 mRNA and protein expression significantly increased by IL-1β treatment in both Hs578T cells and MDA-MB231 cells. In addition, IL-1β-induced cell migration and invasion also increased in Hs578T and MDA-MB231 cells. On the other hand, the levels of basal and IL-1β-induced IL-8 and MMP-3 expression were decreased by zerumbone.

Conclusion: IL-1β induces the migration and invasion of breast cancer cells through IL-8 and MMP-3 expression. These effects are significantly suppressed by zerumbone. Therefore, we suggest that zerumbone may act as a useful therapeutic agent for treatment of triple negative breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-19.
Abstract P2-12-07: The correlation between Myriad Genetic Laboratories, Inc. mutation prevalence table and clinicopathological characteristics of breast cancer patients in Okinawa
Authors: Arakaki M , Kamada Y , Uehara K , Tamaki K , Tamaki N
Published: August 2014

Introduction

The two major susceptibility genes for breast cancer and ovarian cancer, BRCA1 andBRCA2 were discovered in 1994 and 1995, respectively. Various risk prediction algorithms and models have been developed to identify putative BRCA1/2 mutation carriers. Myriad Genetic Laboratories, Inc. released Mutation Prevalence Tables (http://www.myriad.com/lib/brac/brca-prevalence-tables.pdf#search = ‘Myriad+Genetic+Laboratories%2C+Inc.+Mutation+Prevalence+Table’) through its clinical testingservice. To the best of our knowledge, this is the first study to examine the correlation between this risk prediction model and clinicopathological characteristics of breast cancer patients.

Methods

The cases were 148 female breast cancer patients without any previous breast cancer history who initially visited Nahanishi Clinic Okinawa in Okinawa, Japan, between May 2012 and March 2013. The median ages were 55 years old (26-84). We examined the correlation between Myriad Genetic Laboratories, Inc. released Mutation Prevalence Tables and clinicopathological characteristics including age, ER, PgR, HER2, triple negative status, histological grade and Ki67. The presence of ER and PgR was determined by nuclear staining with positive cases defined as more than 1% staining according to ASCO CAP. With regard to HER2 evaluation, membranous staining was graded as 0-1+, 2+, and 3+. Samples scored as 2+ were subjected to FISH. Positivity was defined as a HER2:CEP17 signal ratio>2.2. Ki-67 labeling index was obtained by selecting the hot spots after evaluation at low power magnification and counting 1000 tumor cells in the hotspots.

Results

There was statistically negative correlation between the risk prediction rates and age (r = -0.480, r2 = 0.230, p<0.001). The risk prediction rates of ER negative and positive were 2.93±4.12% and 4.06±9.53% with statistically significant differences (p = 0.049).On the other hand, tendency was detected in PgR status (p = 0.058), and the risk prediction rates were 3.21±1.92% of PgR negative and 4.24±3.34% of PgR positive, respectively. The risk prediction rates of triple negative cases and non triple negative cased were 2.58±0.94% and 4.06±3.11% with statistically significant differences (p<0.001). There were not statistically significant differences in HER2 status, histological grade and Ki67, respectively.

Conclusion

Previous studies demonstrated that BRCA1/2 mutation was associated with triple negative and high grade malignant breast cancer. However, the results of this study suggested that Myriad Genetic Laboratories, Inc. released Mutation Prevalence Tables was not associated with triple negative and/or high risk breast cancer patients in Okinawa.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-12-07.
Abstract P2-14-08: Plasma pro-enkephalin and pro-neurotensin for the risk prediction of incident breast cancer in healthy women
Authors: Melander O , Orho-Melander M , Almgren P , Manjer J , Hedblad B , Engström G , Struck J , Nilsson P , Bergmann A , Belting M
Published: August 2014

Experimental settings have indicated that Neurotensin regulates both satiety and breast cancer growth. Proneurotensin 1-117 (pro-NT), which stems from the same precursor as Neurotensin, has been developed as a reliable plasma surrogate biomarker for the unstable Neurotensin and has been shown to be associated with the development of incident breast cancer.

Enkephalins and related opioid peptides may negatively regulate carcinogenesis and the growth of breast tumors through stimulation of the immune tumor defense system as well as direct inhibitory effects on breast cancer cells. However, little is known about their role in the development of breast cancer in humans. Enkephalin can be assessed in plasma by measuring a stable surrogate marker, Pro-Enkephalin A 119-159 (pro-ENK).

OBJECTIVE:

To test if plasma pro-ENK in healthy women is associated with the development of incident breast cancer and if it adds information to pro-NT for the risk prediction.

DESIGN, SETTING, AND PARTICIPANTS:

We measured pro-ENK and pro-NT in fasting plasma from 1929 women (mean age 58 +/- 5.9 years) of the population based Malmo Diet and Cancer Study (MDCS), who were free from breast cancer prior to the baseline exam. We used Cox proportional hazards models to relate pro-ENK and pro-NT to first breast cancer events (n = 123) within 15 years of follow-up.

RESULTS:

Decreasing concentrations of pro-ENK were significantly associated with the risk of women to develop breast cancer: Women belonging to quartiles 3, 2 and 1 of pro-ENK compared to those of quartile 4 had Hazard ratios (HR) for breast cancer of 1.41 (0.74-2.69), 2.3 (1.27-4.14) and 3.19 (1.82-5.62).

Pro-NT: As compared to women belonging to the 1st quartile of pro-NT, women belonging to quartiles 2, 3 and 4 of pro-NT had HRs for the devlopment of breast cancer of 1.24 (0.69-2.24), 1.61 (0.92-2.82) and 2.37 (1.4-4.01).

Pro-ENK significantly added prognostic value to pro-NT (p = 0.00006) and vice versa (p = 0.00002). The HR for women with pro-ENK in the 1st quartile and pro-NT in the 4th quartile (high risk group) was 4.17 (2.48-7.03) as compared to women with pro-ENK in quartiles 2-4 and pro-NT in quartiles 1-3 (low risk group). Women with one of the biomarkers in high risk still had a slightly increased risk (HR 1.71 (1.16-2.52)) as compared to the low risk group.

CONCLUSION:

Biomarker based risk prediction for the development of breast cancer is significantly improved, when plasma pro-ENK is added to pro-NT.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-14-08.
Abstract P2-16-09: Retrospective analysis of long-term survivors with HER2+ metastatic breast cancer (MBC) treated with trastuzumab in a community setting
Authors: Jones S , Tseng W-Y , Saravanan S , Santos E , Dhanda R , Rembert DS , Yap MA , Lalla D , Brammer M
Published: August 2014

Background: The median survival for patients (pts) receiving trastuzumab (T) in the metastatic setting is approximately 3 years. There are limited data on real world use and outcomes in T treated pts who live longer than 3 years. The objective of this study was to identify and characterize pts with HER2+ MBC who initiated treatment with T (alone or in combination) in a community setting and to determine their treatment patterns and outcomes, including duration of treatment, overall survival (OS) and time to permanent discontinuation of T. Methods: A retrospective observational study was performed using the IKnowMed electronic medical record (EMR) used by the US Oncology Network with the primary time period of 2007 through Dec. 2012. Eligible pts had at least 2 visits at practice locations with full EMR capability. Pts on T when the EMR was implemented had chart review to determine the dates of diagnosis and start of T treatment. Results: The study population included 1856 women with HER2+ MBC who started T (alone or in combination with chemotherapy or hormonal therapy); 873 presented with MBC and 983 developed recurrence following diagnosis of early-stage disease. The median age was 58, range 23 to 96, 59% had ER+ cancer, 64% were postmenopausal and 35% had multiple sites of disease at presentation. Median OS for the entire group was 40.9 months and the median time to permanent discontinuation of T was slightly less, at 39.9 months. Interestingly, the median OS and duration of T use were similar in the recurrent MBC population and in the population who presented with de novo MBC. The proportion of pts receiving T and OS by year are presented (Table). Thirty-two percent of pts are still alive at 6 years, with 17% continuing to receive T.

Outcomes of 1856 Patients Treated with TrastuzumabYear1356Pts still receiving T (%)82%53%27%17%OS (%)84%54%36%32%

Ongoing analysis will evaluate whether there are pt and treatment characteristics that may predict for longer term OS. Conclusions: Using an EMR database we identified 1856 women with HER2+ MBC who initiated treatment with T (alone or in combination) with one third still alive at 5 years and 27% still on T. Future research that focuses on understanding the characteristics of this population can potentially improve care for women with HER2+ MBC with T and newer anti-HER2 agents.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-09.
Abstract P2-16-11: Impact of adjuvant trastuzumab (T) with chemotherapy on breast cancer specific and cardiac outcomes in older women with small, node-negative HER2-positive breast cancer
Authors: Cadoo KA , Morris PG , Patil S , Norton L , Hudis CA , McArthur HL
Published: August 2014

Introduction:

For women with high risk early breast cancer that overexpresses HER2, the role of adjuvant T with chemotherapy is well established. Although the benefits of this approach in women with small, node negative tumors are less well defined, we previously published a retrospective sequential cohort study that suggested that T with chemotherapy is active in this setting. However there are few data about the safety and efficacy of adjuvant T in older women with small, node negative HER2+ breast cancer. Thus, this we conducted a retrospective study of breast cancer specific and cardiac outcomes for this subset.

Methods:

From our previously reported dataset, we identified women > 60y with <2 cm, node-negative HER2+ breast cancer. We identified a “no-T” cohort of 32 women diagnosed Jan ‘02 - May ‘05 and a “T” cohort of 39 patients diagnosed May ‘05 - Dec ‘08. Electronic medical records were reviewed to examine risk factors and incidence of cardiotoxicity as well as patient outcomes including distant disease-free survival (DDFS) and overall survival (OS).

Results:

Women in the two cohorts had similar baseline characteristics including cardiac risk factors (Table 1). There were no cardiac events in the no-T group. In the T group, 3 patients discontinued T due to a cardiac event: 1 with asymptomatic decline in ejection fraction (EF), 1 with atrial fibrillation and dyspnea, and 1 with symptomatic EF decline associated with myocardial infarct and valvular disease. Patients in both cohorts had excellent disease control at a median follow up of 9y and 6y for the no-T and T cohorts respectively. The 3y DDFS numerically favors the T cohort, the confidence intervals are broad and overlapping (Table 1). There were no detectable differences in OS between groups. In our previous report (not selected for age), DDFS at 3yrs was 95% (90-99) and 100% in the no-T (N = 106) and T (N = 155) cohorts respectively.

Conclusion:

In this small retrospective study, older women with small, node negative HER2+ breast cancers had excellent disease control and a low risk of cardiotoxicity. The possible benefits of T in this setting are consistent with prior reports uncontrolled for age.

Table 1 No Trastuzumab N = 32 N (%)Trastuzumab N = 39 N (%)Tumor Size (cm), median (range)1.4 (0.1-2.0)1.3 (0.5-2.0)Multifocal Disease6 (19)4 (10)Grade 324 (75)33 (85)ER Positive20 (63)20 (51)Age, median (range)66 (60-85)65 (60-82)BMI, median (range)24.7 (18.2-34.2)27.3 (18.2-47.1)Chemotherapy16 (50)39 (100)Radiotherapy23 (72)25 (64)Hypercholesterolemia11 (34)18 (46)Hypertension12 (38)13 (33)3yr DDFS (95% CI)91% (74-97)97% (83-100)3yr OS (95% CI)97% (80-100)97% (83-100)

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-11.
Abstract P3-03-07: Combination of eribulin and PI3K inhibitors in triple negative and HER2 expressing breast cancer cell lines results in synergistic growth inhibition and enhanced inhibition of the PI3K pathway
Authors: Luyimbazi D , Luu T , Xing Q , Yan J , Tully D , Han E , Yip RML , Yim JH
Published: August 2014

Background. Patients with triple negative breast cancer (TNBC) have high levels of pAkt expression and activation of the PI3K-mTOR pathway. Eribulin is a microtubule-targeting agent with benefits in treating taxane and anthracycline refractory breast cancer. Our objective was to evaluate its efficacy in inhibiting PI3K pathway activity and cell growth both alone and in combination with PI3K/MTOR inhibitors BEZ 235 and BKM 120.

Methods. TNBC cell lines MDA468, BT549, HS587T, MDA231, and HER2 expressing breast cancer cell line SKBR3 were used for this study. Both MDA468 and BT549 have PI3K- related mutations. The tetrazolium salt, 3-4,5 dimethylthiazol-2,5 diphenyl tetrazolium bromide (MTT) assays were used to assess growth inhibition after 72 hour treatment with eribulin, BEZ 235 and BKM 120 both alone and in combination. Combination indices (CI) generated by Chou-Talalay plots were used to quantify synergy. Western blots were used to evaluate the expression of phosphorylated Akt (pAkt), S6K1 (pS6K1) and S6 (pS6) from 30 min to 24 hours of treatment at different doses.

Results. Eribulin has IC50 ranging from 60 pM to 300 pM, BEZ 235 has IC50 ranging from 50 nM to 80 nM, and BKM has IC50 ranging from 500 nM or higher. Standard dilutions of eribulin in combination with BEZ 235 resulted in synergistic growth inhibition (CI<1) in both MDA468 and BT549 cells at all doses tested, but required higher concentrations (500 to 2000 nM) for BKM 120. Western blot analysis for all cell lines treated with eribulin showed pAkt inhibition by eribulin alone with doses as low as 1 nM and as early as 4 hours. PI3K inhibitor alone confirmed inhibition of pAkt, pS6K1 and pS6 at early time points with feedback increase in pAkt at 24h. While both BEZ 235 and BKM 120 treatment increased pAkt in a dose dependent fashion at 24 hours, combination treatment with eribulin showed a dose dependent decrease in pAkt.

Conclusion. Our study shows significant synergistic growth inhibition with the combination of eribulin and PI3K inhibitors. This may be related to inhibition by eribulin of the feedback increase in pAkt seen with PI3K inhibitors alone at later time points. These findings point to a potential role for combination therapy of both eribulin and PI3K inhibitors in treating refractory metastatic disease.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-03-07.
Abstract P3-06-24: Decrease of mortality from breast cancer in Brazil: Data from a population-based cancer registry
Authors: Ismael GV , Coradazzi AL , Mattos ÉR , Cantarelli A , Beato CM , Ikoma MV , Veneziano DB , Caldeira JRF , Segalla JGM
Published: August 2014

Background: The incidence rates of breast cancer in developed countries increased between 1980 and 1990 due to use of breast cancer screening and lifestyle changes. Since 2000, however, breast cancer incidence has decreased in these areas, which is possibly attributed to less exposure to hormone replacement therapy. Since 1990, the United States, United Kingdom, and France have reported a reduction in breast cancer related deaths, mainly due to improved early detection and more effective therapies. Data considering the trend of incidence and mortality rates in Brazil are scarce. Herein, we have evaluated these trends in a population-based cancer registry.

Methods: We have collected the data from annual rates of breast cancer incidence (BCI) and mortality from breast cancer (MBC) in a population-based cancer registry in Jau (Sao Paulo State, Brazil) and joinpoint regression analysis was used to evaluate the incidence and mortality trends. Annual average percentage change (AAPC) was estimated and increase or decrease in rates was considered when AAPC was statistically significant (p value less than 0.05), otherwise it was considerable stable.

Results: BCI and MBC rates are exposed in Table 1 and 2, respectively.

Table 1. BCI in Jau-SP, from 2000 to 2009.YearNumber of casesBCI (/100,000 women)20003160.9720012944.6520024367.4520033857.6520043143.8820053957.2320062739.2020073744.0320083946.6220093839.33

AAPC for BCI was -3.02% (p = 0.1226) and for MBC was -9,77% (p = 0.0082).

Conclusion: This data from a population-based cancer registry demonstrates that in Jau (Sao Paulo, Brazil), from 2000 to 2009, BCI was stable and MBC has decreased.

Table 2. MBC in Jau-SP, from 2000 to 2009.YearBreast Cancer Related DeathsMBC (/100,000 women)20001320.3620010915.4720021219.8620031216.5620040813.652005067.9520061318.6220070911.312008078.382009076.96

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-24.
Abstract P3-09-03: Final result of randomised controlled phase II study of the efficiency of palonosetron, aprepitant, and dexamethasone for day1 with or without dexamethasone on days2 and 3
Authors: Kosaka Y , Sengoku N , Minatani N , Kikuchi M , Nishimiya H , Waraya M , Enomoto T , Kuranami M , Tanino H , Watanabe M
Published: August 2014

Background: Emesis is one of the major non-hematologic toxicity caused by chemotherapy. The control of Chemotherapy Induced Nausea and Vomiting (CINV) is conducted to a life lengthening. Recently, CINV is controlled by the second generation 5-HT3 receptor blocker (Palonosetron; PALO) and a NK-1 receptor antagonist (Aprepitant; APR). It has been shown that dexamethasone (DEX) with 5-HT3 receptor blocker improves acute / delayed CINV. However, it has not been determined the medication schedule for DEX with PALO and APR. The purpose of this study is evaluated the efficiency of palonosetron, aprepitant and dexamethasone for day1 with or without dexamethasone on days2 and 3. This is final result of current study.

Methods: Breast cancer patients who administered anthracyclin drug regimen have been eligible from April, 2011 to June, 2013. The patients were randomised to group A (PALO/APR/DEX one day) and group B (PALO/APR/DEX three days).

Trial designAprepitant125mg80mg80mg  Palonosetron0.75mg    dexamethasone9.9mg6.6 mg or placebo6.6 mg or placebo  Chemotherapydo    days12345

Eighty patients were estimate as study samples. The primary endpoint was a complete response (CR) rate of vomiting, the secondary endpoint was a complete control (CC) rate of vomiting.

Results: Eighty two patients were enrolled in this study. There was not inferiority about CR rate of five days after chemotherapy (81.1% of group A, 82.1% of group B). CC rate of group A (62.2%) was better than that of group B (46.2%). However, CC rate was no significant difference between group A and B. There was no significant difference about any level of nausea between group A and B.

Conclusions: One day of dexamethasone with Palonosetron and Aprepitant treatment is enough to control the emesis of high emetogenic chemotherapeutic agents.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-03.
Abstract P3-09-11: Acupuncture for the treatment of lymphedema in breast cancer patients: A pilot study in Korean women
Authors: Jeong YJ , Kim MS , Jang JI , Bong JG , Park SH , Kwon HJ , Park YS , Kwon OC , Shin IH
Published: August 2014

Purpose: Lymphedema is a troublesome complication of breast cancer treatment. Recent studies suggest that acupuncture is effective in improving lymphedema in breast cancer patients. The purpose of this study was to assess the feasibility and safety of acupuncture for treatment of lymphedema in Korean breast cancer patients.

Methods: This was a prospective, single-arm, observational study. Participants received 18 sessions of acupuncture, delivered 3 times a week for 6 weeks. Patients were evaluated 1 week before treatment commenced (baseline), once a week during treatment, and 4 weeks after the final acupuncture session. Recruitment was performed from September 2012 through December 2012, and 9 breast cancer patients presenting with lymphedema of the upper limb ipsilateral to surgery were enrolled. The primary outcome measure was severity of lymphedema assessed by stages of lymphedema, visual analogue scale (VAS) and circumferential measurements of the upper extremity. The secondary outcome measure was quality of life assessed by a self-administered questionnaire using the SF-36 Questionnaire.

Results: Acupuncture significantly reduced the severity of lymphedema assessed by VAS (p<0.001) as well as circumferential measurements of upper extremity (p<0.001). Four weeks after the final treatment, symptoms were not aggravated. SF-36 scores remained significant for health status at the end of treatment (p = 0.018). No serious adverse events occurred in 162 treatment sessions and during the 4-week follow-up period.

Conclusions: Our results showed the feasibility and safety of acupuncture for the treatment of lymphedema in Korean breast cancer patients. These findings suggest that acupuncture is a useful complementary and alternative treatment for improvement of lymphedema itself and related symptoms in breast cancer patients. A randomized controlled prospective study with a larger sample size is required to clarify the efficacy of acupuncture for such patients in Korea.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-11.
Abstract P3-15-10: Human neuronal model to study chemotherapeutic-induced peripheral neuropathy
Authors: Dolan ME , Wing C , Komatsu M , Delaney SM , Wheeler HE
Published: August 2014

Chemotherapy-induced peripheral neuropathy is the major dose-limiting toxicity for several anti-cancer drugs including taxanes, platinating agents and microtubule inhibitors. In general, animal models have been used to study neuropathy. Our goals are twofold: 1) to create a human model for study of chemotherapeutic induced neuropathy using iCell Neurons derived from human induced pluripotent stem cells (iPSCs) and; 2) to elucidate the molecular genetic mechanisms underlying chemotherapeutic induced peripheral neuropathy by identifying genetic variants and genes that increase the likelihood of this devastating adverse event. We have used this model system to perform functional studies on candidate targets of interest from clinical studies of chemotherapeutic induced neuropathy. Upon treatment of iCell Neurons with increasing concentrations of paclitaxel (0.001-100 μM) for 72 hours, we identified a reproducible 3-5 μm (12-14%) decrease in cell median neurite process length and a 13-19 μm (10-13%) decrease in cell total neurite outgrowth per order of magnitude increase in drug. The same concentrations of vincristine and cisplatin for 72 hours result in a decrease in cell median neurite process length of 6-18% and 2-4% per order of magnitude increase in drug, respectively. No decrease in neurite length is observed with hydroxyurea, a drug that does not result in neuropathy. Paclitaxel binds to beta-tubulin to exert its cytotoxic effect and genetic variants within the promoter of TUBB2A were shown to be associated with paclitaxel induced neuropathy (Clin Cancer Res, 18(16):4441-8, 2012). As a proof of concept, we have shown that decreased expression of the beta-tubulin isotype TUBB2A by siRNA transfection causes decreased median neurite process length (interaction P = 2.0 × 10-4) and decreased total neurite outgrowth (interaction P = 6.2 × 10-10) of iCell Neurons 48 hours post-paclitaxel treatment. To determine clinical relevance, we have developed a protocol to collect blood of breast and ovarian cancer patients experiencing severe paclitaxel-induced peripheral neuropathy and matched patients without neuropathy following similar paclitaxel regimens to create iPSCs and eventually neurons. We hope to create a resource of these cells for the scientific community.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-15-10.