bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P4-15-03: Patterns of relapse following re-irradiation of the breast using partial breast brachytherapy (PBB)
Authors: Chadha M , Boachie-Adjei K , Boolbol SK , Kirstein L , Osborne MP , Tarter P , Harrison LB
Published: August 2014

Purpose: This study is undertaken to evaluate the patterns of relapse among patients with a prior history of irradiation where the RT field included the breast, and who received re-irradiation using PBB for a localized second cancer event in the breast using partial breast.

Materials and Methods: Twenty-seven patients were enrolled in an IRB approved study. Nineteen patients had prior history of breast cancer treated with lumpectomy and external beam therapy (ERT), and 8 patients had prior history of mantle RT. All patients underwent lumpectomy with negative margins and received a median dose of 45Gy PBB. The median time interval between the primary breast cancer diagnosis and the second cancer event in the ipsilateral breast is 94-months (range 28-months to 211-months). The median time between mantle RT and the breast cancer is 245 months.

Results: At a median follow up of 73 months following lumpectomy and PBB 14.8 % (4/27) patients developed a local recurrence and were salvaged by mastectomy. The 5-year Kaplan Meier local disease-free survival and mastectomy-free survival is 100% and 81%, respectively. Remarkably, one third of patients with prior history of mantle RT developed third primary cancers (pancreas, lung and renal). All patients with the third primary cancers died free of any relapse from the breast cancer. None of the patients with prior history of breast cancer developed a second malignancy, and 3/21 developed distant metastases.

Conclusions: In appropriately selected patients with prior history of lumpectomy and ERT for breast cancer we observed a high rate of local control and freedom from mastectomy. Patterns of relapse among patients with prior mantle RT suggest that breast conservation and PBB was appropriate for treating early stage disease. Breast conservation therapy did not have a detrimental effect on breast cancer specific outcome and eventual patient survival. Patients motivated for breast conservation may have an alternative to mastectomy at initial diagnosis.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-15-03.
Abstract P5-01-11: ‘Same-day diagnosis’ of women suspected of breast cancer: success rate and impact on diagnostic quality and patients' anxiety levels
Authors: Barentsz MW , Wessels H , van Diest PJ , Pijnappel RM , van der Pol CC , Witkamp AJ , van den Bosch MA , Verkooijen HM
Published: August 2014

Introduction: Uncertainty about a breast cancer diagnosis is a stressful event. As such, many initiatives have been undertaken to reduce the time of uncertainty by providing ‘same-day diagnosis’ for patients suspected of breast cancer. However, only few studies have evaluated the feasibility of ‘same-day diagnosis’ diagnosis, while the impact of ‘same-day diagnosis’ on diagnostic accuracy and patient anxiety has hardly been studied at all. This study aims to evaluates feasibility, diagnostic accuracy and impact on patients' anxiety of ‘same-day diagnosis’ of patients suspected of breast cancer.

Materials and Methods: In November 2011, the ‘same-day diagnosis’ system was implemented in our hospital. This system consists of completing the following items on the day of the first visit: 1. Clinical examination, imaging (mammography, ultrasound), and (if necessary) FNA or core needle biopsy2. High speed processing of biopsy specimens using Leica Peloris tissue processor3. Multidisciplinary evaluation of clinical, imaging and histological findings4. Communication of the final diagnosis and treatment plan to the patient

All patients presenting for ‘same-day diagnosis’ are entered prospectively in a database. Feasibility of ‘same-day diagnosis’ is evaluated, and reasons for failure are scrutinized. Diagnostic quality of ‘same-day diagnosis’ is evaluated by linking all patients to PALGA (Dutch National Pathology Database) six months following the day of diagnosis, in order to identify false negative results (i.e. missed cancers) and false positive results (i.e. ‘cancers’ turned out to be benign during further work-up). Impact of ‘same-day diagnosis’ on patient anxiety is measured by the 4-item State Trait Anxiety Inventory, which is filled out by patients on several occasions on the day of diagnosis as well as during the first seven days following diagnosis.

Results: Between November 2011 and May 2012, 266 women were eligible for ‘same-day diagnosis’. Fifty-eight patients (22%) were diagnosed with breast cancer. Overall, 80% of the patients received a final diagnosis within one day. For patients with cancer, this proportion was somewhat lower, i.e. 71%. Accuracy of ‘same-day diagnosis’ and impact on patients' anxiety are currently under study.

Conclusion: ‘Same-day diagnosis’ is feasible for the far majority of patients suspected of breast cancer. Evaluation of implementation of ‘same-day diagnosis’ on diagnostic quality and impact on patient anxiety is crucial. Updated results will be presented in December 2012.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-01-11.
Abstract P5-03-04: Effect of aging on the function and transformation of murine mammary stem cells
Authors: Bandyopadhyay A , Dong Q , Wang D , Gao H , Wu A , Yeh I-T , Sun L
Published: August 2014

Epidemiological studies have shown that the risk of getting breast cancer progressively increases with age. A woman is 100 times more susceptible to develop breast cancer in her 60s than in her 20s. A better understanding of altered cellular and molecular mechanisms leading to the development of sporadic breast cancers as a result of aging are urgently needed for its prevention and treatment in growing population of older women. Recent research implicated that adult mammary stem cells (MaSCs) might be responsible for the initiation and progression of certain types of breast cancer. But no studies have been reported on how lifelong exposure of MaSCs to endogenous and environmental stresses during aging compromises their self-renewal and differentiation function and predispose them to neoplastic transformation either spontaneously or after carcinogen exposure. In our study, we have investigated the effect of progressive aging and carcinogen exposure on MaSC number and function in a murine model. The FACS isolated MaSC enriched basal cells, characterized by their immunophenotype (Lin−CD49fhighCD24med) were utilized to evaluate MaSC frequency and function during aging by in vitro mammosphere formation and 3D-ECM sphere differentiation assay as well as by in vivo cleared mammary fat pad transplantation (IVT). The results of our study showed that the percentage of MaSCs analyzed by both FACS profile and in vitro assays, increased steadily with increasing age observed at 2, 7, 17 and 25 month-old C57BL/6 mice. Subsequent IVT using mammosphers or 3D structures formed by young (4 months) and old MaSCs (28 months) derived from C57BL/6 mice showed similar in vivo functional mammary gland regenerative capacity indicating similar self-renewal/differentiation ability between young and old MaSCs. However, we found that the regenerated glands from old MaSCs had significantly higher number of spontaneous pre-neoplastic lesions (52.0%) than those from young MaSCs (18.3%). Significantly, MaSC frequency was also increased by the in vivo exposure of a carcinogen, N-Methyl-N-Nitrosourea (MNU, 25 mg/kg body weight, once a week for three consecutive weeks), in old mice with no effect on total mammary cell number. Furthermore, the old MaSCs expanded by MNU treatment were still capable of in vivo regeneration with similar success rate as that of normal old MaSCs. But, we observed increased frequency of hyperplasia and dysplasia in the regenerated glands initiated by MNU treated old MaSC. Our results indicate that MaSCs might be the precursors of preneoplastic lesions and old MaSCs appear to be predisposed to premalignant transformation, which is enhanced by the exposure to a DNA damaging agent.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-04.
Abstract P5-03-05: Histone deacetylase (HDAC)-inhibitor mediated reprogramming drives cancer cells to the pentose phosphate metabolic pathway
Authors: Debeb BG , Larson RA , Lacerda L , Xu W , Smith DL , Ueno NT , Reuben JM , Gilcrease M , Krishnamurthy S , Buchholz TA , Woodward WA
Published: August 2014

Recent studies have shown that energy metabolism in human pluripotent cells contrasts sharply with energy metabolism in differentiated cell types. Specifically, it has been shown that nuclear reprogramming from somatic cells to induced pluripotent stem cells is associated with a switch from oxidative to glycolytic metabolism. Whether a metabolic switch also occurs in reprogrammed/dedifferentiated breast cancer cells is unknown. Moreover, the function of the metabolic state in stemness is poorly understood and no data are available on whether breast cancer stem cells (CSCs) are metabolically different from committed cancer cells. Herein we demonstrated that HDAC inhibitors reprogram committed single aldefluor negative breast cancer cells into aldefluor positive cells (10.3 ± 2.8 vs 21.3 ±3.7% untreated vs treated P <0.05, representing an average of 5 single cell derived clones) and promoted tumor initiation from non-initiating committed cells (p = 0.004). Further, induced stem-like cells were resistant to taxol and salinomycin, a drug previously described to target CSCs. These reprogrammed cancer cells have enhanced activity of the pentose phosphate pathway (PPP) with upregulation of G6PD expression and activity and higher levels of NADPH and ROS. Hypothesizing that CSCs may favor the PPP in order to survive and self renew, we used G6PD inhibitors, 6-AN and Imatinib, to target mammosphere formation and aldefluor activity in HDAC inhibition induced stem-like cells. Not only was there a significant decrease in mammospheres from reprogrammed cells, the aldefluor activity was totally blocked at a concentration that does not affect proliferation. This work demonstrates that HDAC inhibition mediated cancer cell dedifferentiation promotes metabolic reprogramming and highlights an FDA approved drug that targets metabolism in stem cell plasticity. Further functional endpoint studies are underway to validate these findings.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-05.
Abstract P5-04-08: Identifying and characterizing human kinases for novel regulators of epithelial-mesenchymal transition in breast cancer cells
Authors: Li L , Azizian N , Li W
Published: August 2014

The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by breast cancer cells. Recently, a few kinases, such as FYN and c-Met, were reported to participate in regulating EMT. However, the roles of the majority of ∼700 human kinases in EMT and breast cancer progression are still unknown. Here we carried out human kinase cDNA screens to identify novel regulators of EMT. Many unknown EMT regulators and a few known ones such as PI3K, PDGFRA, FYN and c-Met, were found to up-regulate mesenchymal marker vimentin. Some also increase fibronectin and N-cadherin expression in kinase-transducted human mammary gland epithelial cells (HMLER). At the same time, these HMLER cells acquired mesenchymal phenotypes, such as increased in vitro migration activity, enhanced capability to survive and proliferate in growth factor deprivation condition or under drug treatments. RT-PCR results also exhibited increased expression of some EMT transcriptional regulators, such as ZEB1, Snail and Slug, which suggested our selected kinases may regulate EMT through these transcription factors. Interestingly, FACS analysis also showed a substantial increase in CD44hiCD24− population in these kinase-transducted HMLER cells. The increase of CD44hiCD24− mesenchymal phenotype could be attributed to increase of standard form CD44 (CD44s) and decrease of the variant form CD44 (CD44v8-10). And this alternation was associated with down-regulation of ESRP1 and ESRP2, two splicing factors that regulate CD44 splicing and EMT. Therefore, these selected kinases may be considered as novel regulators of EMT, and may aid the development of new prognostic markers or drug targets for breast cancer progression.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-04-08.
Abstract P5-08-01: Investigating the role of BRCA1 in sensitivity to GRN163L, a telomerase template antagonist
Authors: Phipps EA , Gryaznov SM , Herbert B-S
Published: August 2014

Background: BRCA1 is a tumor suppressor gene with a variety of functions related to safeguarding genomic integrity. The regulation of telomere length is also crucial in maintaining genomic stability, with critically short telomeres leading to telomere uncapping, end-to-end fusions, activation of the DNA damage response, and cell cycle arrest. The objective of this study was to determine whether GRN163L, a telomerase template antagonist currently in clinical trials, has enhanced activity in BRCA1 mutant breast or ovarian cancer cell lines compared to BRCA1 wild-type breast/ovarian cancer cell lines.

Methods: We utilized a panel of breast and ovarian cancer cell lines harboring both N-terminal and C-terminal BRCA1 mutations. This cell line panel included two isogenic cell line pairs reconstituted with wild-type BRCA1 (BRCA1 mutant: HCC1937 and UWB1.289; BRCA1 wild-type reconstituted: HCC1937+BRCA1 and UWB1.289+BRCA1). We assessed the effects of GRN163L or a mismatch oligonucleotide (MM) on telomerase activity and telomere length using the TRAP (Telomere Repeat Amplification Protocol) and TeloTAGGG (Roche) assays, respectively. Clonogenic survival assays, proliferation assays, and immunofluorescence were used to assess cellular responses to GRN163L and their molecular mechanisms.

Results: All cell lines tested exhibited a dose-dependent response to treatment with GRN163L, but not a mismatch control oligonucleotide. The majority of the cell lines tested showed gross morphological changes as early as 12 hours following inhibitor treatment. Progressive telomere shortening was evident after 3-week treatment with GRN163L, but not after treatment with MM. We observed differential sensitivity between BRCA1 mutant and wild-type isogenic cell line pairs to GRN163L in clonogenic survival assays. GRN163L pretreatment was synergistic with cisplatin in UWB1.289 and UWB1.289+BRCA1 cells. Simultaneous treatment with GRN163L and doxorubicin was synergistic in HCC1937 and HCC1937+BRCA1 cells. Long-term (12-week) treatment with GRN163L preferentially induced complete cell death in HCC1937 (BRCA1 mutant) breast cancer cells compared to HCC1937 cells reconstituted with wild-type BRCA1. One-week treatment with GRN163L was sufficient to induce γ-H2AX foci, with more γ-H2AX positive cells in the UWB1.289 BRCA1 mutant cell line.

Conclusions: Telomerase inhibition may be a viable treatment in BRCA1 mutant breast or ovarian cancers. These data provide insights into further investigations on the role of BRCA1 in the DNA damage response to GRN163L or combination treatment.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-08-01.
Abstract P5-10-09: Prediction of Trastuzumab treatment response for HER2-positive breast cancer by microRNA profiling
Authors: Sato F , Wang Z , Ueno T , Myomoto A , Takizawa S , Masuda N , Mikami Y , Shimizu K , Tsujimoto G , Toi M
Published: August 2014

[Background and Aim] Although Trastuzumab has been used for HER2(+) breast cancer, the treatment response of Trastuzumab therapy depends on unknown mechanisms among individual cases. In order to avoid unnecessary adverse events and to lighten financial burden for patients, pre-treatment prediction of trastuzumab treatment response would be beneficial for patients. Thus, in this study, we develop a prediction algorithm using microRNA expression profile of breast cancer tissues. [Materials and Methods] Eighty-three breast cancer patients who underwent trastuzumab-chemo combined therapy before operations were enrolled with written informed consent. FFPE specimens of pre-treatment core needle biopsy samples were collected, and regions containing cancer and adjacent stromal cells were laser-microdissected. Total RNA samples extracted from the microdissected specimens were subjected for microRNA microarray (3D-Gene®, Toray, Japan) analysis. Among these 83 patients, 39 cases had pCR (complete response in IDC regions regardless presense of DCIS without lymphnode metastasis), and the other 44 cases did not. According to the pCR/non-pCR information, we develop a prediction model using 35 signature microRNAs by a SVM technique. Prediction accuracy assessed by Leave-one-out validation was AUROC=0.889. The 35 signature microRNAs for trastuzumab treatment response included 7 out of 8 let-7 family members and miR-125a-5p/b-5p. [Conclusion] microRNA profile could predict treatment response of trastuzumab-chemo combined therapy for HER2(+) breast cancer, and the developed prediction algorithm might be a useful tool for clinical decision making.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-09.
Abstract P5-12-02: Tangled in the Breast Cancer Web: An Evaluation of the Usage of Web-based Information Resources by Breast Cancer Patients
Authors: Nguyen SKA , Ingledew P
Published: August 2014

Background: Increasingly cancer patients are researching web-based information to inform their clinical encounter with physicians. The use of the internet by breast cancer patients is incompletely characterized in the literature. The purpose of this study was to characterize the use of the internet by breast cancer patients describing the way they search for, and the impact of, web-based information on the clinical encounter.

Methods: From September 2011 to January 2012, breast cancer patients presenting at a tertiary cancer centre waiting to see their oncologist completed a written 23-question survey. Answers were closed and open-ended. Mixed-methods were used to interpret the quantitative and qualitative data.

Results: 81 patients were approached and 56 completed the survey. Forty-five (80%) respondents used the internet and of those, 32 (71%) respondents searched for breast cancer information. Patients who searched for internet breast cancer information (users) were younger than those who did not use the internet (p = 0.01). All respondents used Google as their principal search engine and “breast cancer” was the most commonly used search term. Twenty (62%) users accessed sites from a reputable source and 19 (59%) users viewed top search engine hits. To evaluate quality, 15 (47%) users referred to website author credentials and 13 (41%) users examined references. All users sought information with respect to treatment and three-quarters sought information on prognosis. The internet influenced treatment decision making for 30 (66%) users. Twenty-six (80%) users felt the information increased their knowledge of breast cancer and it influenced treatment decision making for 16 (53%) patients.

Conclusions: This study highlights search patterns and factors used by patients in seeking web-based breast cancer information. Physicians must appreciate that breast cancer patients use the internet for information and address discrepancies between the information sought and that which is available.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-12-02.
Abstract P5-13-01: Does empowering patients improve accrual to breast cancer trials?
Authors: Arnaout A , Kuchuk I , Bouganim N , Verma S , Clemons M
Published: August 2014

BACKGROUND Many international oncology professional and patient advocacy groups recommend that a minimum of 5% of eligible new patients should be entered into a clinical trial. Unfortunately, physician and patient related barriers translates to a much lower accrual rate in reality. We performed a prospective single arm pilot study evaluating the efficacy of implementing various physician and patient related strategies in enhancing clinical trial accrual.

METHODS All patients with newly diagnosed breast cancer seen at the breast surgery clinic were eligible for the study. Patients were offered information packages by their surgeons on non-surgical clinical trials that they might be eligible for, prior to their initial oncologist visit. Oncologists were informed of the information given to the prospective patient consultation via email and chart flagging. Patient were then given a questionnaire assessing the feedback on this method of introducing clinical trials. The primary outcome was the number of patients consenting to clinical trials. Secondary outcomes included the number of patients actually enrolling in clinical trials, screen failure rate, and overall patient satisfaction with this method of potentially enhancing accrual to clinical trials.

RESULTS 36 patients consented to this pilot study. 51% of oncologists mentioned the clinical trials to the patients. For those patients with which clinical trials were discussed, 72% went on to consent for a trial of which 31% were ultimately found to be ineligible (screen failure rate). The overall 14% clinical trial enrolment was significantly higher than our historical average of 7%. 100% of the patients found that the information package very helpful and was noted to reduce anxiety (39%) and empower (31%) the patients. 19% of the patients felt that this information should have been offered by the oncologist during the initial consultation as opposed to the surgeon prior to the oncology visit.

CONCLUSIONS The findings of this study could have a major impact on the way that cancer centres across the world approach patients for clinical trial options. Physicians remain an important barrier to trial accrual. The results of this study demonstrate that combined patient and physician centered approach to clinical trial enrolment may be the most effective.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-13-01.
Abstract P5-14-01: Accrual of underrepresented minority women to breast cancer clinical trials in Inland Empire, California.
Authors: Yuan Yuan , Uppala Padma Tadi , Morgan John W , Garberoglio Carlos A , Lum Sharon
Published: August 2014

Withdrawn by Author

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-14-01.
Abstract P5-15-01: Cost-effectiveness of gene expression profiling for ductal carcinoma in-situ (Oncotype DCIS Score)
Authors: Alvarado MD , Harrison BL , Solin LJ , Ozanne EM
Published: August 2014

BACKGROUND: Ductal carcinoma in-situ (DCIS) affects nearly 50,000 women each year. More than 75% of women who receive lumpectomy (BCS) for DCIS undergo whole breast radiation (XRT), which is known to prevent local recurrences. A molecular assay for DCIS has recently been validated, that identifies low-risk biology and may give insight into the need for adjuvant XRT. We sought to determine the cost-effectiveness of the Oncotype DCIS Score™ for risk stratification in newly diagnosed DCIS.

METHODS: We conducted a cost-effectiveness analysis of using this molecular assay (validated in the E5194 study) compared to standard clinical assessment to determine treatment recommendation for XRT. A Markov model was developed in TreeAge Pro 2011 and simulated relevant outcomes over a lifetime horizon for 55-year-old women. For those in the intervention arm who are stratified by the assay, it was assumed that 75% of women (low DCIS score) did not receive XRT and had local risk of recurrence (LRR) of 12%; 25% were intermediate or high risk by the DCIS score (LRR of 26%) and received 6 weeks of XRT with an assumed LRR of 13%. For those in the standard care arm who are stratified by clinical assessment, an assumed 25% did not receive XRT and had LRR of 15.4%; 75% received 6 weeks of XRT with an estimated LRR of 7.7%. Recurrence rates were based on ECOG 5194 and assumed 50% reduction with XRT. Utilities were derived from literature. Direct medical costs were obtained from Medicare fee schedule; indirect costs (time and transportation for XRT) were ascertained.

RESULTS: On average, the intervention (assay) strategy was less costly than the clinical assessment strategy by approximately $1000/patient, with similar life expectancies (17.15 vs 17.11, respectively) and quality-adjusted life-years (QALYs) (16.777 vs 16.789). The incremental cost-effectiveness ratio (ICER) for changing strategy from the assay to clinical assessment was approximately $95,000/QALY, at the upper limit of the societal accepted willingness-to-pay threshold.

CONCLUSIONS: Based on the conservative assumptions that the benefit of XRT is independent of biology and that at least 75% of patients in E5194 would typically be offered XRT, the assay strategy is more cost-effective than standard clinical assessment. Additional research is needed to better understand health state utilities associated with less treatment as it pertains to risk of recurrence. Further validation studies of the assay are needed to accurately assess radiation benefit across all risk groups.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-15-01.
Abstract P5-15-03: Cost-effectiveness of ‘radioguided occult lesion localization’ (ROLL) versus ‘wire-guided localization’ (WGL) in breast conserving surgery for non-palpable breast cancer: results from a randomized controlled multicentre trial
Authors: Postma EL , Koffijberg E , Verkooijen HM , Witkamp AJ , van den Bosch MA , van Hillegersberg R
Published: August 2014

Background: Accurate pre-operative localization of non-palpable breast cancer is essential to achieve complete resection. Radio-guided occult lesion localization (ROLL) has been introduced as an alternative for wire-guided localization (WGL). Although efficacy of ROLL has been established in a RCT, cost-effectiveness of ROLL compared with WGL is not yet known.

Objective. To determine whether ROLL has acceptable cost-effectiveness compared with WGL.

Methods. An economic evaluation was performed alongside a randomized controlled trial (ClinicalTrials.gov, number NCT00539474). Women (>18 years) with histologically proven non-palpable breast cancer and eligible for breast conserving treatment with sentinel node procedure were randomized to ROLL(n = 162) or WGL (n = 152). Empirical data on direct medical costs was collected, and changes in quality of life were measured over a 6 months period. Bootstrapping was used to assess uncertainty in cost-effectiveness estimates, and sensitivity of the results to the missing data approach was investigated.

Results. In total, 314 patients with 316 invasive breast cancers were enrolled. On average ROLL required the same time as WGL for the initial procedure (119 vs. 118 min.), resulted in a 7% higher re-interventions risk (27% vs. 20%, p = 0.163), a 13% higher complication risk (30% vs. 17%, p = 0.006) but showed similar health effects (difference 0.00 QALYs 95%CI (−0.04 to 0.05). Total costs were also similar for ROLL and WGL (+ €26 per patient 95% CI-250 to 311).

Conclusion. ROLL is comparable to WGL with respect to both costs and quality of life, and will therefore not lead to more cost-effective medical care.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-15-03.
Abstract P5-17-01: Bevacizumab (B) in the adjuvant treatment of breast cancer - first toxicity results from Eastern Cooperative Oncology Group trial E5103.
Authors: Miller KD , O'Neill A , Dang C , Northfelt D , Gradishar W , Sledge GW
Published: August 2014

Background: A previous feasibility trial (E2104 – Ann Oncol 23(2):331–7,2012) suggested incorporation of B into anthracycline-containing adjuvant therapy was feasible but ongoing cardiac monitoring was required to define the true impact of B on cardiac function.

Methods: Patients (pts) were assigned 1:2:2 to one of three treatment arms. In addition to doxorubicin and cyclophosphamide followed by weekly paclitaxel, patients received either placebo (Arm A – AC>T) or B during chemotherapy (Arm B - BAC>BT), or B during chemotherapy followed by B monotherapy (15 mg/kg q3wk) for an additional 10 cycles (Arm C – BAC>BT>B). Randomization was stratified and B dose adjusted for choice of AC schedule (classical q3wk − 15 mg/kg; dose dense(dd) q2 wk − 10 mg/kg). When indicated, radiation and hormonal therapy were administered concurrently with B (for Arm C pts). The primary cardiac endpoint was the incidence of clinically apparent cardiac dysfunction (CHF)defined as symptomatic decline in left ventricular ejection fraction (LVEF) to below the lower limit of normal (LLN) or symptomatic diastolic dysfunction as assessed by independent review. Cumulative toxicity data as of Jan 23, 2012 are presented.

Results: From 11.07 to 2.11, 4994 pts were enrolled. Median age was 52; 80% received ddAC. Chemotherapy associated toxicities including myelosuppression (Grade 4 neutropenia 16/20/19%) and neuropathy (Grade ≥ 3 8/8/8%) were similar across all arms. Grade ≥ 3 hypertension/thrombosis/proteinuria/hemorrhage was reported by 7/3/<1/<1% of B-treated pts. 99 pts developed CHF, most commonly reported at the post-AC or post-T evaluation. After a median follow-up of 26 months, the cumulative incidence of clinical CHF at 15 months from randomization in Arm A/B/C was 1.0/1.7/2.9% respectively. Median age of CHF pts was 57; median baseline LVEF of CHF pts was 60.

Conclusion: Incorporation of B into anthracycline and taxane containing adjuvant therapy results in a significant but small increase in clinical CHF. The rate of clinical CHF is similar to that predicted by E2104 (2.5–2.9%) and reported In the FDA label for anthracycline pre-treated pts(3.8%). No unexpected toxicities were encountered.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-01.
Abstract P5-17-07: Influence of bevacizumab on local-regional recurrence in triple negative breast cancer
Authors: Prendergast BM , De Los Santos JF , Barrett OC , Forero A , Falkson CI , Urist MM , Krontiras H , Bland KI , Meredith RF , Keene KS , You Z , Carpenter JT
Published: August 2014

Background: Triple negative breast cancer (TNBC) comprises 15–20% of newly diagnosed invasive breast cancers and has been associated with an elevated risk of both local-regional recurrence (LRR) as well as distant failure. Bevacizumab (BEV) has been shown to improve pathologic complete response rates in the setting of neoadjuvant chemotherapy (NCT), but its effect on LRR remains undefined. This study reports the impact of adding BEV to standard breast cancer therapy in TNBC patients treated at a single institution.

Methods: One hundred and eighty-five consecutive TNBC patients treated at the University of Alabama Birmingham from May 2005 to August 2010 were reviewed. Thirty-one TNBC patients treated with chemotherapy (CT) and BEV on prospective studies were matched (1:2) with 62 TNBC patients treated with CT alone, controlling for age, stage, and use of radiation (RT). The Kaplan-Meier method was used to estimate LRR, distant metastasis-free survival (DMFS), and overall survival (OS), and cohorts were compared using Cox proportional hazards models and the 2-sided log-rank test.

Results: Mean age was 47 and 46 years in the cohorts with and without BEV, respectively. Stage in each cohort was as follows: 32% stage I, 61% stage II, and 7% stage III. Use of adjuvant RT was 81% in each cohort (25/31 BEV, 50/62 no BEV). BEV was delivered with NCT in 17 patients (55%) and with adjuvant CT in the remaining 14 patients (45%). Eleven patients (35%) completed an additional 1 year of maintenance therapy with BEV. LRR occurred in 2 (6%) patients treated with BEV vs. 16 (26%) treated with CT alone (HR = 0.25, 95% CI 0.06–1.07, p = 0.04). Distant recurrence occurred in 3 (10%) patients treated with BEV vs. 11 (18%) patients in the CT group HR=0.6, 95% CI 0.2–1.8, p = 0.48). There were 2 (6%) deaths in the BEV group vs. 12 (19%) in the CT alone group (HR = 0.55, 95% CI 0.13–2.3, p = 0.19).

Conclusions: In a matched-pair analysis of TNBC patients, the addition of BEV to conventional breast cancer management was associated with a reduction in LRR. Further prospective study is necessary to examine the impact of BEV on local-regional control in TNBC.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-07.
Abstract P5-18-03: Clinicopathological features among patients with HER2-positive breast cancer with prolonged response to trastuzumab based therapy
Authors: Vaz-Luis I , Seah D , Olson E , Metzger O , Wagle N , Sohl J , Litsas G , Burstein H , Krop I , Winer E , Lin NU
Published: August 2014

Background: HER2-positivity is a predictor of benefit from trastuzumab (TRZ), but fails to depict the observed interpatient variability in terms of treatment (tx) duration. In this study we described the relationship between clinicopathological features and TRZ tx duration.

Methods: A retrospective consecutive series of 343 HER2+ breast cancer (BC) patients (pts) treated with TRZ at the Dana-Farber Cancer Institute from 1999–2008 was identified. 139 pts treated with 1st line TRZ-based tx were selected for analysis. Pts who received any non-TRZ prior tx for metastatic disease were excluded. TRZ tx duration was defined as time from start of 1st line therapy to the 1st day of 2nd line therapy or death. Central nervous system (CNS) progression with TRZ maintenance was not considered change of tx. Pts were divided equally into 3 groups based on the duration of 1st line tx distribution. Short-term responders (STR) were on the 1st line tx for <7 months (m), intermediate responders (IR) 7–15m and long responders (LTR) for >15m. An additional group of extremely LTR (ELTR) was defined as being in the 90th percentile of tx duration (>37m). Descriptive analysis was performed; fisher exact test, Kruskal-Wallis and logistic regression methods were used to compare groups.

Results: Median follow-up time since metastatic diagnosis was 4 years (y) (range 0–11). Median age at diagnosis was 47y (22–83), 25% of stage I-III pts at diagnosis received adjuvant/neoadjuvant TRZ. The median disease free interval (DFI) was 20m (0–172), median number of metastatic sites was 2(1–5), 68% of pts had visceral disease. Median duration of 1st line tx was 10m (2–105). TRZ was given with CT in 86%, hormone tx in 6% and as monotherapy in 9%. 25% of pts developed CNS progression and continued tx. There were only small absolute differences for clinicopathological characteristics among STR, IR and LTR.

ELTR had a median 1st line TRZ tx duration of 49m (37–105) and similar clinicopathological features to LTR. A higher proportion of LTR had hormone receptor (HR)-positive disease compared with STR, however no significant association between LTR and STR was found for HR status, DFI and visceral involvement.

Conclusions: TRZ tx duration varies widely in the 1st-line advanced setting. No clinicopathological features were associated with TRZ tx duration. Our results suggest that despite CNS progression some pts continue to have long term benefit to TRZ tx. A major research priority is to identify molecular predictors of benefit and resistance to anti-HER2-based therapies.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-03.
Abstract P5-18-06: Trastuzumab emtansine in HER2-positive metastatic breast cancer: pooled safety analysis from seven studies
Authors: Diéras V , Harbeck N , Budd GT , Greenson JK , Guardino E , Samant M , Chernyukhin N , Smitt M , Krop IE
Published: August 2014

Background: The antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1) combines the antitumor activities of trastuzumab with intracellular delivery of the cytotoxic agent DM1 and represents a new approach to therapy for HER2-positive MBC. Recently, the first phase 3 data have been reported with significant improvements in PFS (9.6 vs 6.4 months; HR=0.650; P<0.0001) and lower incidence of grade ≥3 adverse events (AEs) (57% vs 41%) vs capecitabine + lapatinib (Blackwell 2012). This pooled analysis reports the overall safety profile of T-DM1 3.6 mg/kg q3w in 882 patients treated with T-DM1.

Methods: Data were included from treated patients in 7 studies of single-agent T-DM1 3.6 mg/kg q3w: 1 phase 1 study in previously treated MBC (TDM3569g, Krop 2010, n=15 treated at 3.6 mg/kg q3w); 3 phase 2 single-arm studies in previously treated MBC (TDM4258g, Burris 2011, N=112; TDM4374g, Krop 2012, N=110; TDM4688g, Gupta 2011, n=51); 1 randomized phase 2 study in previously untreated MBC (Hurvitz 2011, TDM4450g/BO21976, n=69); 1 extension study (TDM4529/BO25430, n=43 from parent studies); and 1 phase 3 study in MBC previously treated with trastuzumab and a taxane (EMILIA, Blackwell 2012, n=490). Data were analyzed in 4 groups: (1) all T-DM1-treated pts (7 studies, N=882), (2) pts originally enrolled in single-arm studies (n = 288), (3) T-DM1 pts from TDM4450g (n = 69), and (4) T-DM1 pts from EMILIA (n = 490).

Results: Among all pts (N = 882), median age was 53 years (range 25–85 years); 52.7% had ≥3 metastatic sites; 81.7% had received prior treatment for MBC; and the median number of prior non-endocrine agents for MBC was 3.0 (range 0–19). All-grade AEs occurring in ≥25% of patients were fatigue (45.4%), nausea (42.3%), headache (28.7%), thrombocytopenia (28.7%), and constipation (25.5%). Grade ≥3 AEs occurring in ≥2% were thrombocytopenia, increased AST, increased ALT, fatigue, hypokalemia, and anemia. Table 1 describes the grade ≥3 incidence of these AEs, as well as selected AEs with known association to T-DM1 or potential risk based on the components of T-DM1 or on preclinical data.

Conclusions: The safety profile of T-DM1 3.6 mg/kg q3w was consistent across the studies and the different patient populations with HER2-positive MBC. Additional analyses on hepatic transaminase increases and those exploring potential associations between thrombocytopenia and hemorrhage will be presented.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-06.
Abstract P5-18-08: Identification of ErbB2 function in the heart: implication for anti-ErbB2 therapy in breast cancer
Authors: Perry M-C , Eichner LJ , Dufour CR , Muller WJ , Giguère V
Published: August 2014

The ErbB2 receptor tyrosine kinase is essential for cardiac development during embryogenesis. The importance of its signaling in the adult heart was revealed by an unexpected cardiotoxic side effect of trastuzumab, a monoclonal antibody against ErbB2 used in the treatment of breast cancer. Considering that trastuzumab-associated cardiotoxicity is usually largely reversible, we hypothesized that ErbB2 signaling in the heart is important to maintain cardiac homeostasis.

As genetic experiments showed that ErbB2-deficient embryos die at mid-gestation, whereas conditional inactivation of ErbB2 in the heart leads to early and severe cardiac dysfunction, the role of ErbB2 in the mature heart can not be analyzed in those animal models. Thus, we chose an ErbB2 hypomorph (HP) mouse model in which ErbB2 is expressed at only 10% of its endogenous level to study the role of ErbB2 in the adult heart. Histopathological analyses of the heart in this model revealed that at birth, the ErbB2 HP mice have similar heart mass and cardiomyocite size as the control animals. However, we found that the rapid growth of the heart during early postnatal development is impaired in ErbB2 HP mice, indicating that the heart is unable to increase cell size in order to adapt to the pressure overload that mice face following birth. This incapacity of the ErbB2 HP heart to maintain homeostasis eventually leads to the development of cardiac dysfunction in this model, as characterized by a decrease of the left ventricular function. Microarray and ChIP-seq analyses were applied to identify the ErbB2-responsive pathways which may explain the phenotype observed. Taken together, our results demonstrate that ErbB2 signaling is required for the physiological adaptive response of the mature heart to pressure burden. The results generated by this study reveal the biological function of Erbb2 in the adult heart, but also provide important information for devising strategies to prevent and mitigate the cardiotoxic effects of Trastuzumab treatment, allowing for the potential use of this drug to treat all cancer patients overexpressing ErbB2.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-08.
Abstract P5-18-13: Inhibiting telomerase to reverse trastuzumab (T) resistance in HER2+ breast cancer
Authors: Miller KD , Steding CE , Prasad N , Rojas LA , Herbert B-S
Published: August 2014

Background: Preclinical studies have shown the combination of imetelstat (GRN163L), an inhibitor of telomerase, and T results in synergistic growth inhibition and restoration of T sensitivity in T-resistant cells (Clin Can Res 12(10):3184–92, 2006). Here we translate those findings to the clinic with the first-in-man phase I trial of imetelstat+ T in patients (pts) with T-refractory HER2+ metastatic disease.

Methods: T (6 mg/kg q3 wk) was administered with increasing doses of imetelstat (240/300/375 mg/m2 q3 wk) using a standard 3+3 dose escalation design. Maximum Tolerated Dose (MTD) was based on toxicity observed during cycle 1. Responding or stable pts continued treatment until progression. Tumor biopsy and bone marrow aspirate for biologic correlates were obtained at baseline and prior to cycle 2. Limited pharmacokinetics (PK) for T and imetelstat were included.

Results: Ten pts were enrolled; median age was 54 (28–64). Patients were extensively pre-treated with the number of prior regimens ranging from 3 to >12. Prior cytotoxic therapies included anthracyclines (n = 9), taxanes (n = 9), vinorelbine (n = 8), capecitabine (n = 8), gemcitabine (n = 6), ixabepilone (n = 4), and eribulin (n = 4). Prior anti-HER2 targeted therapies included trastuzumab (n = 10), capecitabine (n = 8), T-DM1 (n = 6), and pertuzumab (n = 1). Therapy was well tolerated; no treatment related grade 4 toxicities were observed. Myelosuppression was limited to one pt with Grade 2 anemia and one each with Grade 2/3 thrombocytopenia. MTD was not reached. There were no objective responses; 2 pts. in cohort 3 had SD. Serial tumor biopsies and bone marrow aspirates have been analyzed for 7 pts (cohort 1: 001–004; cohort 2: 005–007; cohort 3: analysis ongoing). Tumor hTERT (p = ns) and phosphorylated HER2 (p = 0.03) decreased after treatment in nearly all pts. Bone marrow S-phase did not change consistently with treatment.

Conclusion: The combination of trastuzumab + imetelstat is well tolerated and results in decreases in HER2 phosphorylation similar to that seen in preclinical models. Additional biologic correlates and PK analyses are ongoing. Further study of this combination in less heavily pre-treated patients is planned.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-13.
Abstract P5-18-22: Long-term survival of patients with HER2 metastatic breast cancer treated by targeted therapies.
Authors: Fiteni F , Villanueva C , Bazan F , Chaigneau L , Cals L , Dobi E , Montcuquet P , Nerich V , Limat S , Pivot X
Published: August 2014

Purpose: HER2 targeted therapies have substantially improved outcomes of patients with HER2 positive metastatic breast cancer (MBC). Medical records of patients with HER2 positive MBC achieving long survival were reviewed to describe their clinical characteristics and to assess whether curability is possible.

Patients and methods: One thousand and seven hundred patients with MBC were treated between 01/01/2003 and 31/05/2012 in the 5 hospitals from the Franche-Comte region. All 217 patients with HER2 positive MBC region were retrospectively studied.

Results: Among this population of HER2 positive MBC, 56 patients (26%) survived longer than 5 years. The characteristics of these long survivors were the following: median age at diagnosis was 55 years old (range, 33–87); 20 patients (35,7%) were metastatic at presentation; 20 patients (35,7%) had received adjuvant chemotherapy; the median disease-free interval was 17 months; brain, liver, lung, bone metastases were observed in 4 (7%), 19 (34%), 13 (23%), 23 (41%) in cases at occurrence of metastatic disease, respectively; tumours were hormonal receptors positive in 39 cases (70%) of these patients.

A total of 16 (29%), 7 (12,5%), 7 (12,5%) and 26 (46%) cases had received 1, 2, 3 or more lines of chemotherapy at metastatic setting. The proportion of HER2 targeted treatment was 79%, 61%, 50% in first, second and third line, respectively. All patients received trastuzumab or lapatinib for their disease and 18 patients (32%) were given an anthracycline containing regimen.

There were 7 complete response (CR), there were all observed after one line of chemotherapy based on trastuzumab combined with a taxane in all cases. Among these 7 patients, all continued trastuzumab after CR and all RH+ patients received hormonotherapy after CR. Among these 56 patients, 35 (62,5%) were still alive at the date cutoff in 31/05/2012.

Conclusion: A significant proportion of patients with HER2 positive MBC were long survivors. Prospective clinical trials in this subset of patients should take into account this high number of patients with favorable outcome to achieve conclusion in term of survival. Can one consider the curabiblity of some MBC patients with HER2 overexpression?

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-22.
Abstract P5-20-01: A randomized double-blind phase II study of the combination of oral WX-671 plus capecitabine vs. capecitabine monotherapy in first-line HER2− negative metastatic breast cancer (MBC).
Authors: Goldstein LJ , Oliveria CT , Heinrich B , Stemmer SM , Mala C , Selder S , Bevan P , Harbeck N
Published: August 2014

Background: uPA and its inhibitor PAI-1 play a key role in tumor invasion, metastasis and tumor growth. High levels of uPA and PAI-1 in breast tumors are statistically significant prognostic factors of disease-free (DFS) and overall survival (OS), which were validated at the highest level of evidence, as well as predictors for benefit of adjuvant chemotherapy. WX-UK1 is an active site competitive inhibitor of uPA with an inhibition constant in the submicromolar range. WX-671 (upamostat) is an oral prodrug of WX-UK1. In preclinical animal tumor models, both WX-UK1 and WX-671 have been shown to reduce the growth rate of implanted tumors, to inhibit invasion, and reduce metastases. This current proof of concept study is designed to substantiate the anti-metastatic properties of upamostat for patients appropriate for first line therapy for MBC.

Methods: Female patients aged >18, with HER2 negative MBC appropriate for first line monotherapy with capecitabine, with adequate performance status, organ function, bone marrow reserve without brain metastases were eligible. Patients were randomized in a double-blind fashion to receive upamostat (200mg orally daily for 21 days) plus capecitabine (1000 mg/m2 orally twice daily for 14 days) vs. capecitabine (1000 mg/m2 orally twice daily for 14 days) in 3 week treatment cycles until progressive disease or unacceptable toxicity. The primary endpoint is to evaluate the efficacy of the combination of upamostat plus capecitabine compared to monotherapy as assessed by comparison of progression free survival. The secondary objectives are OS, objective response rates, safety and tolerability, and to assess the pharmacokinetics (PK) of upamostat and capecitabine when combined.

Results: Between August 2008 and April 2011,132 patients were enrolled. 17 patients are still receiving treatment. 26% of the patients are characterized as triple negative, 13% as only Estrogen Receptor (ER) positive and 4% as only Progesteron Receptor (PR) positive. 57 % of the patients are ER and PR positive.

Conclusions: Progression free survival, response rates and safety will be reported. This abstract is being submitted as a placeholder. A completed abstract will be submitted when the analyses are completed.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-01.