bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of airplane travel on women treated for breast cancer.
Authors: Kilbreath S , Ward L , Lane K , McNeely M , Williams E , McKenzie D , Refshauge K , Peddle C , Battersby K
Published: December 2010

Abstract #1119

Background: Many patient materials promulgate lifestyle adaptations purported to minimize risk of lymphedema. One factor often mentioned is development or exacerbation of lymphedema due to airplane travel. The aim of this study was to describe prospectively the effect of airplane travel on women treated for breast cancer, traveling to Caloundra, Qld., Australia to attend a dragon boat regatta.  Methods: Pre and post data were obtained from 63 women traveling from Canada to Australia, and from 12 women traveling within Australia. 54% were treated for breast cancer on their dominant side, 63% underwent mastectomy with or without reconstruction, 77% underwent axillary node dissection, and 21% wore a compression sleeve during flight; 94% trained at a moderate to vigorous intensity for the regatta. Single frequency bioimpedance analysis (BIA; XCA; Impedimed Inc.®) was used to determine the inter-limb difference in upper limb extracellular fluid. BIA is highly reliable and has high sensitivity and specificity for increased extracellular fluid accumulation. Change in ratio >0.05 for women without lymphoedema is of clinical significance. Women were measured within 2 weeks of their flight to Caloundra, immediately on arrival in Caloundra, and for 46 women, within 6 weeks of return to Canada.  Results: Airplane travel did not have a significant effect on the upper limb BIA ratio, either between the pre and post flight (t75= -0.355; p=0.72) or between the pre and follow-up measures (t44=.241; p=0.811).    Overall, the BIA post ratio increased from the pre measure by ≤0.02 in 48 women; 0.02 to <0.05 in 12 women; 0.05 to <0.10 in 10 women; and >0.10 in 5 women (Fig 1). In Figure 1, symbols in grey-shaded area represents women who did not have lymphedema prior to flight but presented with it post flight and the dashed lines indicate previously established cut-offs for criteria for detection of lymphedema. Dotted line on each graph is the line of agreement. The 6 symbols in the grey shaded area (Fig 1) represent women from the international group; their change in BIA ranged from 0.05 to 0.28. Follow-up measures were available on 5 of these women, and indicated that 4 were below the cut-offs for lymphedema. All 6 women had undergone mastectomy and axillary clearance of their lymph nodes and for 5, surgery was on their dominant side. Only 3 of the women wore a compressive sleeve on the plane.  Discussion: For the majority of women who undertake moderate to vigorous upper limb exercise, airplane travel did not have a significant impact on extracellular fluid ratio. Acknowledgment: Impedimed for funding and equipment.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1119.
Behavioral change in African American breast cancer survivors: results and challenges.
Authors: Young RF , Zora D , Deutsch-Keahey D
Published: December 2010

Abstract #1126

Background: African American breast cancer survivors have higher cancer mortality and greater prevalence of health risk behaviors than Caucasians. They are appropriate candidates for a behavioral intervention but few lifestyle change studies focus exclusively on this population.  Methods: 37 breast cancer survivors enrolled in a healthy living study that sought to implement a comprehensive lifestyle and breast care intervention to an African American target population. The 12-month intervention included behavioral change classes and individualized telephone counseling. Questionnaires and anthropometric measurement determined diet, exercise, cancer history and care, and psychosocial characteristics (quality of life on FACT-G; breast cancer and obesity awareness; self-efficacy). At entry subjects averaged: 60 yrs. Of age; 7 yrs. Post-breast cancer diagnosis; 190 lbs. Body weight; BMI = 32; 5.1 fruit/vegetable servings daily; 48% diagnosed at cancer stage I; 33% calories from fat in diet.  Results: 68% completed the 12-month study. Subjects who attended <2 of 8 class sessions had higher BMI at intake (p < .05). Oldest subjects were less likely to complete the study (p <.05). Behavioral changes at 4-months (after 8 classes) were: +3.5 hrs. weekly exercise; -2.37 % fat in diet; - 1 lb. weight. 12-month outcomes (after telephone counseling) were: average weight loss 1.44 lbs; small reduction in BMI; rise in moderate or more physical activity; improved cancer and obesity awareness; improved FACT-G scores (p = .07); reduced self efficacy for behavioral change (p < .05) as subjects realized the implications of improving eating and exercise habits. Neither length of time since cancer diagnosis nor age effected the extent of behavioral change.  Discussion: African American breast cancer survivors entered, and many completed, a intensive health behavior intervention. Overall, study completers improved their exercise behavior, food choices, and lost a modest amount of weight. Some early changes (4 months) were sustained over 12 months. Subjects with higher BMIs at entry provided the most challenge; they attended fewer class sessions and were less likely to lose weight.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1126.
NCIC CTG MA.17: hormone receptor expression of in-breast recurrences and contralateral primary breast cancers arising on aromatase inhibitors.
Authors: Moy B , Tu D , Shepherd LE , Palmer MJ , Ingle JN , Goss PE
Published: December 2010

Abstract #1134

Background: The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of ER+ (but not ER-) invasive breast cancers in healthy women at high risk for developing breast cancer. Aromatase inhibitors (AIs) given as adjuvant therapy to treatment-naïve or post-tamoxifen patients significantly reduce the risk of in-breast recurrences (IBRs) and contralateral breast cancers (CBCs) and are currently in clinical trials for breast cancer prevention (NCIC CTG MAP.3 and IBIS-II). It is hypothesized that SERMS inhibit promotion of ER+ breast cancer whereas AIs may reduce both ER+ and ER- breast cancer by inhibiting both tumor initiation and promotion. Little is known about the characteristics of IBRs and CBCs that arise on AI therapy. We present the ER/PR expression and clinicopathologic features of IBRs and CBCs that occurred on MA.17.  Methods: We examined ER/PR status of IBRs and CBCs that arose on letrozole vs. placebo among women enrolled in MA.17, a placebo-controlled (PLAC) trial of letrozole (LET) following 5 years of tamoxifen in postmenopausal women with early stage breast cancer.  Results: Seventy-one patients (pts) developed an IBR and 87 developed a CBC on trial. Consistent with results previously reported, fewer IBRs (LET 20 vs PLAC 51) and CBCs (LET 35 vs PLAC 52) were observed in the LET group. ER and PR status is currently available on 35 women with an IBR and 39 with a CBC. The majority of IBRs were ER+ in both the LET and PLAC groups (10/11 [91%] vs 18/24 [75%], respectively; p=NS) but numbers of both ER+ and – IBRs were less in LET group, suggesting that letrozole may decrease both ER+ and ER- IBRs. CBCs that arose on PLAC were more likely to be ER+ than on LET (16/22 [73%] vs 6/19 pts [32%], respectively; p=0.01), suggesting that letrozole predominantly prevents ER+ CBCs. Discordance in ER expression between primary breast cancer and IBRs among women randomized to LET vs. PLAC was observed in 1/11 [9%] and 6/24 [26%] women respectively (p=NS) and between primary breast cancer and CBCs in 12/18 pts [67%] vs. 6/21 [29%] women respectively (p=0.01). Other clinicopathologic characteristics such as grade, tumor size, PR, HER-2/neu, and nodal status of IBRs and CBCs will be presented at the meeting.  Conclusion: Extended adjuvant endocrine therapy with letrozole results in fewer IBRs and CBCs compared with placebo as previously reported. Our data suggests that letrozole may decrease both ER+ and ER- IBRs. Letrozole appears to prevent ER+ CBCs but has little or no apparent effect on the development of ER- CBCs. These results need confirmation in the primary prevention trials of AIs.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1134.
Administrative claims: a novel approach in monitoring long term adherence to anti-hormonal therapy in breast cancer.
Authors: Meguerditchian AN , Watroba N , Roistacher J , Stewart A , Cropp M , Edge SB
Published: December 2010

Abstract #1135

Background:  Anti-hormonal therapy (AHT) is a key component of therapy that improves survival in breast cancer. However, many women do not complete the prescribed treatment course. There is currently limited reliable information regarding long-term adherence to AHT. We hypothesize that health payer administrative claims for prescription benefits may allow more reliable monitoring of AHT use.  Methods:  Claims for women diagnosed with breast cancer between 2001 and 2003 from a single insurance carrier covering about 1/3 of the regional population were matched to disease stage and treatment information from the National Cancer Data Base (NCDB) for women treated at NCDB hospitals in Western New York. Claims were searched for AHT drugs identified by National Drug Codes (NDC). Start date, end date, type of agent, switch in drugs, patterns of discontinuation, and dates of insurance coverage eligibility were recorded. A compliance index was attributed to each patient, reflecting the ratio of AHT claims identified, over the ideal number of claims that should have been recorded based on treatment start date.  Results:   AHT was initiated in 230 women at a median of 165 days from breast cancer diagnosis. Stage was 0: 3.5%; I: 54.3%; II: 33.4%; III: 7%; unknown: <2%. Tamoxifen was the first AHT agent in 66.5% of cases. A switch in agents occurred in 36.1% women. There was a gap in prescription renewal in 57% of patients. The average gap length was 5.9 months. The maximum gap duration was 1 month in 27% of cases; however 16% of patients had a treatment gap of 6 months or more. The annual compliance rate for the study population was 79.6%, 60.9%, 52.7%, 24.1% and 6.9% for each of the 5 consecutive years of treatment. After adjusting for time from start of AHT, the compliance index was ≤0.66 in 50% of women. Less than 20% of patients had an index of 1.0 .  Discussion:   Administrative claims data combined with cancer stage data proved to be effective at defining gaps in use of AHT among breast cancer patients. By applying this strategy, we found that over 50% of women treated with AHT had gaps in treatment averaging 6 months. The annual compliance rate to AHT decreased steadily over each of the 5 years of treatment. Real time monitoring of administrative claims for patients who start AHT can identify those who discontinue treatment and may allow counseling on side effects and benefits and improve treatment compliance and outcome.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1135.
Health-related quality-of-life and psychological distress of postmenopausal breast cancer patients after surgery during the randomized trial, N-SAS BC 03, comparing further tamoxifen with switching to anastrozole after adjuvant tamoxifen for 1 to 4 years: the final results.
Authors: Ohsumi S , Shimozuma K , Ohashi Y , Nomura Y , Aihara T , Takatsuka Y
Published: December 2010

Abstract #1136

Backgroud: Three years ago, we reported the interim results regarding heath-related quality of life (HRQOL) outcomes of the patients who switched their adjuvant endocrine therapy from several years of tamoxifen (TAM) to anastrozole (ANA) and those who had TAM for a total of 5 years in the randomized trial, National Surgical Adjuvant Study of Breast Cancer (NSAS BC) 03. We present the final results of HRQOL and psychological distress in the NSAS BC 03.  Patients and Methods: Recurrence-free postmenopausal breast cancer patients who had received definitive surgery for hormone receptor positive breast cancer, and had been taking TAM for 1 to 4 years after the surgery were enrolled in the randomized trial: N-SAS BC 03. They were randomly assigned to continue TAM for the remaining periods of a total of 5 years or to switch from TAM to ANA and take the latter for the remaining periods. Primary endpoints of the N-SAS BC 03 trial were disease-free survival and adverse events. HRQOL and psychological distress were evaluated as secondary endpoints. They were asked to answer patient-administered instruments to assess HRQOL (FACT-B [breast cancer scale] and FACT-ES [endocrine symptom scale]) and psychological distress (CES-D: Center for Epidemiologic Studies Depression scale) at the randomization (baseline), 3 months, 1 and 2 years after the randomization. HRQOL and psychological distress scores during this period were compared using t-test and the general linear model with correlated errors.  Results: There was no difference in demographic and medical characteristics between the two treatment groups. The response rates of the questionnaires were 98.6%, 97.2%, 90.9% and 78.5% at baseline, 3 months, 1 and 2 years after the randomization, respectively. At baseline 694 patients (346 in the TAM group and 348 in the ANA group) answered them. The total scores of FACT-G, and FACT-ES and the scores of FACT-G physical well-being (PWB) subscale were statistically significantly better in the TAM group than in the ANA group (P = 0.042, 0.038, and 0.005, respectively) after the randomization, while those of FACT-B in the former were marginally better than those in the latter (P= 0.066). However, there were no statistically significant differences between the two treatment groups for the scores of CES-D, and subscales other than PWB of FACT-G, FACT-B, and FACT-ES.  Conclusions: Further TAM treatment after adjuvant TAM for 1 to 4 years may provide postmenopausal breast cancer patients with slightly better HRQOL comparing with switching to ANA.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1136.
Effects of denosumab treatment in breast cancer patients with bone metastases and elevated bone resorption levels after therapy with intravenous bisphosphonates: results of a phase 2 randomized trial.
Authors: Gralow J , Lipton A , Fizazi K , Gao G , Jun S , Yeh H
Published: December 2010

Abstract #1155

Background: Patients with breast cancer-induced bone disease and elevated urine-N-telopeptide (uNTx), a marker of bone resorption, are at increased risk for skeletal complications, disease progression, and death. Receptor activator of NF-kB ligand (RANKL) mediates osteoclastic bone resorption. Denosumab, a fully human monoclonal antibody, inhibits bone destruction by binding and neutralizing RANKL. Denosumab efficacy and safety were assessed in a phase 2, randomized, open-label, active-controlled trial in patients with bone metastases and elevated levels of uNTx after at least 8 weeks of intravenous (IV) bisphosphonate (BP) therapy. We report results in a subset of patients with breast cancer.  Methods: Cancer patients with bone metastases and uNTx >50 nM/mM creatinine [Cr] following at least 8 weeks of IV BP therapy were randomized to continue IV BP therapy every 4 weeks (Q4W) or switch to subcutaneous (SC) denosumab injection (180 mg) Q4W or every 12 weeks (Q12W). The primary endpoint was the proportion of patients who achieved uNTx <50 nM/mM at week 13. Safety was also assessed.  Results: The study population (N = 111) included 46 patients (41%) with breast cancer; the median time since diagnosis of bone metastases was approximately 1 year in both groups. At week 13, 76% of denosumab-treated patients and 33% of IV BP-treated patients had uNTx < 50 nM/mM. Denosumab-induced suppression of uNTx was rapid (as early as 2 weeks after initial treatment), sustained through week 25, and unaffected by baseline uNTx (Table). In the total study population, adverse events of grade 3, 4, or 5 were reported in 25 (71%) IV BP-treated patients and 40 (55%) denosumab-treated patients.    Discussion: Denosumab reduced bone turnover in breast cancer patients with bone metastases and elevated uNTx despite prior IV BP therapy. Phase 3 trials of denosumab in cancer patients with bone metastases are in progress.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1155.
Knockdown of c-Jun N-terminal kinase 1 expression in murine mammary cancer cells leads to an increase in tumor growth and bone metastasis.
Authors: Nasrazadani A , Mitra S , Van Den Berg C
Published: December 2010

Abstract #1156

The c-Jun N-Terminal Kinase (JNK) family of proteins are involved in cell proliferation and apoptosis depending on the specific isoform, cell type, and activating stimuli. The JNK proteins are known as the predominant c-Jun kinases, resulting in AP-1 activation and increased expression of AP-1 transcriptional targets. More specifically, it has been reported that osteoclast differentiation is impaired in jnk1-/- mice. The purpose of this study was to determine whether expression of JNK1 in cancer cells will influence the bone microenvironment during metastatic growth. The 4T1.2 murine mammary cancer cell line was studied as an established model for mammary cancer mediated bone metastasis. Using a JNK1α1 shRNA approach, we observed 75% reduction in expression Orthotopic injection of the shJNK1α1 cells into the mammary fat pad of Balb/c mice significantly increased tumor growth rates and shortened survival compared to the respective empty vector cell line (p<0.0001). Similarly, intra-cardiac injection of the shJNK1α1 cells led to a significant decrease in survival (p=0.003) and an increase in incidence of metastatic lesions in the ribcage (p=0.04). Serum levels of Cathepsin K were assayed as an indicator of bone resorption and was significantly higher in the mice injected with the knockdown cells compared to empty vector controls (p=0.03). Finally, immunohistochemical analysis of bone lesions showed higher expression of ADAM (A Disintegrin and Metalloproteinase) 10 suggesting that the more aggressive phenotype observed with the shJNK1a1 cells may be attributed to the increase in ADAM10 protein expression. Previous studies have shown that ADAM10 that cleaves RANKL into its active soluble form. Further, RANKL expression has been reported to be elevated in breast carcinomas, resulting in osteolysis during metastasis. Indeed our qPCR analysis detected an approximate 2 fold increase in RANKL levels in the shJNK1α1 cells, consistent with this assertion. In summary, these data support that reduction in JNK1a1 expression enhances bone metastasis and ADAM10 expression. We hypothesize that increased RANKL cleavage by ADAM 10 allows RANKL to bind its receptors expressed on nearby osteoclasts further perpetuating the vicious cycle of bone metastasis. These data suggest that bone metastasis may be controlled by inhibiting ADAM10 activity to reduce RANKL induced osteolysis and tumor progression.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1156.
Suppression of bone resorption from odanacatib, a cathepsin K inhibitor, in women with bone metastases from breast cancer, and the effect of concomitant anti-neoplastic treatment on efficacy: a 4-week, double-blind, randomized controlled trial.
Authors: Jensen AB , Wynne C , Ramirez G , Antje L , Nina O , Mehta A , Wang H , He W , Song Y , Berd Y , Lombardi A
Published: December 2010

Abstract #1157

Background: In breast cancer patients with metastatic bone disease (MBD), an osteolytic process releases factors that sustain tumor cell survival and proliferation. Cathepsin (Cat) K inhibition suppresses osteolysis in preclinical models of MBD. This study assessed the efficacy and safety of odanacatib, a potent and reversible selective Cat K inhibitor, in reducing markers of bone resorption in women with breast cancer and MBD depending on concomitant anti-neoplastic treatment.  Materials and Methods: Women with breast cancer and MBD were randomized (double-blind) to oral odanacatib 5 mg daily for 4 weeks or IV zoledronic acid (ZA) 4 mg given once at study initiation. Bone resorption was assessed by urinary N-telopeptide of type I collagen corrected for creatinine (uNTx). A post-hoc analysis of the influence of concomitant therapy (chemotherapy vs hormone therapy) on study medication effects on uNTx was also conducted. Adverse events (AE) were monitored throughout the 4-week study and up to 14 days after last dose.  Results: 43 patients (mean age 60 yrs) received odanacatib (n=29) or ZA (n=14); 40 patients completed all 4 weeks of treatment. 12 (41%) and 17 (59%) patients on odanacatib and 6 (46%) and 7 (54%) patients on ZA received chemotherapy or hormone therapy, respectively; one patient was on both co-therapies and one patient on ZA was not on concomitant therapy. Results for the effect of study medication on uNTx as well as the effects of concomitant therapy on each treatment group are shown in the table; results for the full analysis set were similar. The most common reported AEs were nausea, vomiting, headache, and bone pain, and generally not attributed to study drug.  Conclusions: In women with breast cancer and MBD, the Cat K inhibitor, odanacatib, suppressed markers of bone resorption after 4 weeks of treatment. Mean uNTx was decreased in both treatment groups. The effect on biomarkers observed in this study was seen irrespective of concomitant anti-neoplastic treatment. Odanacatib was generally safe and well tolerated. These results suggest that Cat K inhibition is a potentially important, novel therapeutic approach for treating MBD.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1157.
RAP-011, a soluble activin receptor type IIA IgG-Fc fusion protein, is a novel bone anabolic agent that prevents bone loss and skeletal metastases in a mouse model of metastatic breast cancer.
Authors: Mulivor AW , Barbosa D , Kumar R , Pearsall AE , Underwood KW , Ucran JA , Seehra J , Pearsall R
Published: December 2010

Abstract #1158

Breast cancer cells have a strong propensity to metastasize to bone, resulting in debilitating complications such as intractable bone pain, spinal compression, pathological fractures, or loss of mobility and function. Anti-resorptive agents, such as bisphosphonates, are commonly used to halt the additional loss of bone, but fail to stimulate the formation of new bone to repair lost or damaged bone. Previous data demonstrated that treatment with an activin antagonist, a soluble form of the extracellular domain of the activin type IIA receptor (ActRIIA) fused to a murine IgG-Fc fragment (RAP-011), can restore bone mass in ovariectomized mice with established bone loss and prevent bone loss in a murine model of multiple myeloma.  To investigate the ability of RAP-011 to prevent skeletal metastases in an experimental model, bioluminescent breast cancer cells (MDA-MB-231-luc-D3H2LN) were administered by intracardiac injection into athymic nude mice that had been pretreated for 2 weeks with RAP-011 (10 mg/kg S.C. twice weekly) or vehicle (VEH). At 3 and 5 weeks post-inoculation, RAP-011 treated mice displayed lower levels of hind limb, mandible and lung metastases compared to VEH-treated mice. RAP-011 treated mice had reduced tumor burden (-70%) and increased overall survival by 11 days compared to VEH-treated mice. It was also shown that RAP-011 preserved bone mineral density and increased both trabecular volume (BV/TV +140%, P<0.001) and trabecular number (+15%, P<0.001), compared to VEH. In the VEH-treated mice, BV/TV was lower in bones with a tumor present (0.191) than bones without a tumor (0.276, p=0.1). However, RAP-011 treated mice increased BV/TV to a similar extent in both bones with a tumor (0.598) and bones without a tumor (0.599, p=0.98) compared to the VEH controls (p<0.001).  Taken together, these data suggest that inhibition of activin has the potential therapeutic benefit of improving bone health in patients with cancer related bone loss as well as preventing metastasis of breast cancer. Towards this end, ACE-011, the human analog of RAP-011, is currently in clinical development for the treatment of cancer-related bone loss.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1158.
A randomized phase 2 trial of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with estrogen receptor positive aromatase inhibitor resistant advanced breast cancer.
Authors: Ellis MJ , Dehdahti F , Kommareddy A , Jamalabadi-Majidi S , Crowder R , Jeffe DB , Gao F , Fleming G , Silverman P , Dickler M , Carey L , Marcom PK
Published: December 2010

Abstract #16

Rationale: It has been postulated that aromatase inhibitor (AI) therapy may sensitize ER+ breast cancer to lower doses of estrogen therapy as second-line endocrine treatment for advanced breast cancer (ABC). We therefore conducted a randomized trial of 30mg generic estradiol daily (10 mg t.i.d.- "recommended" dose) versus 6 mg (2 mg t.i.d - "experimental" dose).  Materials and Methods: Major eligibility: Postmenopausal ER+ ABC treated with an AI with 24+ wks progression free survival, or relapse after 2+ yrs of adjuvant AI; RECIST measureable non-bone metastases or WHO assessable bone lesions, with elevated tumor markers >2X ULN. Major exclusions: History venous thrombosis, heart disease, uncontrolled hypercalcemia and fulvestant in the last 12 months. FDG PET scans were conducted at baseline and after 24 hours to assess metabolic flare as a predictor of response (pre-defined as a ≥12% increase in FDG uptake).  Results: Sixty-six patients were enrolled (82% White, 15% Black); mean age 59 years, range 36-84. 34 received 6 mg and 32 received 30 mg. Estradiol levels will be provided at the meeting. There were more patients experiencing grade 3+ SAE on the 30 mg arm versus the 6 mg arm (11 vs. 4; P=0.06) with one venous thrombosis on each arm. There was no difference in total FACT-B QOL scores at one month by treatment arm, QOL decline was associated with more severe estrogen side effects, especially amongst patients on the 30 mg arm (P=0.006). Uterine bleeding was successfully controlled with intermittent progestin therapy. Clinical benefit rates (stable disease at least 24 weeks plus response - intent to treat population) were 25% (CI: 15-37%, 1PR and 7SD out of 32) on the 30 mg arm and 29% (CI: 19-42%, 3PR and 7SD out of 34) on the 6 mg arm. Patients with clinical benefit to estradiol could be retreated with original AI after progression and to date one PR out of three patients with repeat AI therapy noted. There were 44 patients evaluable for the interaction between PET -flare and response. Flare was seen in all responders (3/3), 9 of 13 patients with SD and only 3 of 30 patients with PD (p<0.0001). PPV for PET flare was therefore 12/15 (80%, CI: 61-92%) and NPV 27/31 (87%, CI: 76-94%).   Conclusions: The Protocol Review and Monitoring Committee closed the 30 mg arm early after they concluded that the 6 mg arm was as effective as the 30 mg arm with greater safety. We therefore recommend 6 mg as the appropriate dose for the palliative treatment of advanced ER+ breast cancer. FDG PET flare can be used to identify patients who have a high chance of clinical benefit.  Supported by an AVON NCI Partners in Progress Award: Grant # P30 CA091842-S4.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 16.
Elevated serum levels of the growth factor GP88 are found in breast cancer patients when compared to healthy individuals.
Authors: Serrero G , Tkaczuk K , Zhan M , Tait N , Ilan C , Yue B
Published: December 2010

Abstract #2006

Background: GP88 is an autocrine growth factor that plays a critical role in breast tumorigenesis. GP88 is expressed in human BC tumors in a positive correlation with their tumorigenicity. Increased GP88 expression is associated with resistance to anti-estrogen therapy in ER + cells and with herceptin resistance in Her-2 overexpressing breast tumors. Inhibition of GP88 expression in human breast adenocarcinoma inhibited tumor incidence and growth in nude mice. Immunohistochemical studies have shown that GP88 was expressed in invasive ductal carcinomas in correlation with the expression of poor prognosis markers whereas normal tissues and benign lesions were negative. High GP88 expression in tumor biopsies was accompanied by decreased disease-free survival. Since GP88 can be secreted, we have hypothesized that GP88 could be secreted in the circulation and found in serum. We examined whether GP88 could be found in the circulation and whether GP88 could be elevated in the sera of breast cancer patients when compared to healthy individuals.  Methods: An IRB approved blood sampling study was conducted at the University of Maryland Breast Clinic to determine the serum level of GP88 in healthy volunteers (HV) and breast cancer patients (BC pts). Serum GP88 concentration was determined in triplicate by quantitative enzyme immunoassay. 189 BC pts were accrued. In addition, sera from 18 HV were obtained to establish a GP88 baseline in healthy volunteers. BC patient characteristics: Race: Caucasian- 91, African American-92, Asian-6; median age, 51 (range 29-86), stage I – 48, II - 52, III – 26, IV - 63.  Results: Circulating GP88 was measurable in the serum. Median level of GP88 was 28.7 ng/ml (range 16.6-38.2) in HV; 40.7 ng/ml (range 6.4-100) in early stage (stage 1 –3) BC pts (p- value = 0.007) and 45.3 ng/ml (range 9.8 to 158.4) in stage 4 metastatic BC patients (p-value= 0.0007). Statistically significant increase in circulating GP88 level was found in early stages as well as in metastatic disease. Correlation studies with BC prognostic factors such as stage, tumor size, lymph node involvement, tumor grade and presence of ER and HER-2 will be presented.  Conclusion: GP88 can be detected in the sera of HV and BC pts. Comparison between the two groups of subjects indicates that GP88 level is significantly higher in the sera of BC pts. These studies are important as they identify as a measurable circulating biomarker GP88 that is also a therapeutic target of malignant transformation or malignant progression of breast carcinoma (BC). Future studies will examine whether there is any correlation between the serum level of GP88 and therapeutic response to systemic therapy in breast cancer patients.  This study was supported by grant from MIPS, the Avon Foundation and 1R43 CA 124179-01A1 from the National Institutes of Health.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2006.
Role of radiation induced ß1 – integrin expression in trastuzumab resistance in Her-2 positive breast cancer.
Authors: Thoms J , Sabri S , Lesniak D , Murray D , Abdulkarim B
Published: December 2010

Abstract #2014

Problem Statement: Radiation therapy followed by Trastuzumab-based therapy is the standard of care for Her-2 positive breast cancer (BC) patients, but the molecular basis of this sequential treatment has not been investigated. Fifty percent of early BC patients show primary resistance to Trastuzumab (Tz) and 70% of metastatic breast cancer patients develop Tz resistance within one year. Our in vitro pre-clinical data suggests the role of ß1-integrin, a cell adhesion molecule involved in cell survival, invasion and drug resistance, in Tz resistance. Because ionizing radiation (IR) increases the expression of several integrin subunits in endothelial and tumor cells, we hypothesized that radiation induced ß1-integrin expression could be a potential mechanism of Tz resistance in Her-2 positive BC patients.  Methods: We use Her-2 positive Tz-senstive BC cell lines, SKBR-3 and BT474, which express lower levels of ß1- integrin, than the Tz-resistant cell line JIMT-1.  We analyzed by Immunoblotting the expression of ß1-integrin, phosphorylation and expression of Her-2 and common downstream signaling pathways, PI3-K/Akt and Erk1/2 before and after exposure to IR.  Results: Exposure to IR increased ß1-integrin expression in SKBR-3 and BT474 cells, but not in JIMT-1. Increased ß1-integrin expression in BT474 cells was associated with a substantial increase in phosphorlyation of Her-2, suggesting that ß1-inetgrin may induce transactivation of Her-2. Phosphorylation of Erk 1/2 and Akt, important signal transducers for cell proliferation and survival were also increased.  We will further, investigate Tz sensitivity of SKBR-3 and BT474 following exposure to IR using a blocking antibody for ß1-integrin, and clonogenic survival and XTT assays to evaluate cellular viability and proliferation.  Conclusion: Our results show that IR increased ß1-integrin expression and activation of the PI3-K/Akt pro-survival pathway and suggest that increased b1-integrin expression by IR may confer resistance to Trastuzumab in Her-2 positive cell lines. The physiological relevance of radiation-induced ß1-inetgrin expression in Trastuzumab resistance needs to be further investigated in vivo.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2014.
Tissue inhibitor of metalloproteinases-1 protects the human breast carcinoma cell line MCF-7 S1 against anthracycline-induced cell death by activation of the akt survival pathway.
Authors: Würtz S[ , Schrohl A , Brünner N , Lademann U
Published: December 2010

Abstract #2019

Würtz S and Schrohl A contributed equally.  Background. A large proportion of breast cancer patients are offered chemotherapy following primary surgery, however, many of these patients do not benefit from the treatment. Currently, only few markers exist to predict whether a breast cancer patient will respond to chemotherapy in general or to specific types of chemotherapy. Thus, additional predictive markers need to be identified to ensure a more effective treatment of the patients. In this regard, recent clinical studies performed in our laboratory have demonstrated that high tumor tissue levels of TIMP-1 are associated with a poor response to the most frequently used chemotherapeutic drugs (CMF or anthracyclines) (Schrohl et al., Clin. Cancer Res. 2006 and Klintman et al. manus. in prep.). The purpose of the present study was to investigate the molecular explanation for the clinical findings concerning the predictive value of TIMP-1 using an in vitro approach.  Methods. We stably transfected the human breast carcinoma cell line MCF-7 S1 with the human TIMP-1 gene and established single cell clones expressing different levels of TIMP-1. We then compared the sensitivity of these cells to epirubicin and taxol using cell death and apoptosis assay. In addition, we investigated the signalling pathway that could be involved in the TIMP-1 mediated protection against treatment using western blotting of key molecules.  Results. We found that clones expressing high levels of TIMP-1 were significantly less sensitive to epirubicin. In contrast, no difference in sensitivity to taxol was demonstrated between high and low TIMP-1 clones. When investigating the signalling pathway involved in the difference in sensitivity we found that phosphorylated Akt was highly up-regulated in the high TIMP-1 clones compared to the low TIMP-1 clones following chemotherapeutic treatment.  Conclusion. TIMP-1 protects the MCF-7 S1 cells against anthracycline-induced cell death but not against taxol. Thus, TIMP-1 may be used to discriminate between patients likely to benefit from anthracyclines and patients who should be offered an alternative drug. Furthermore, we found that this protection is probably executed through counteraction of the apoptotic signal by activation of the Akt survival pathway.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2019.
Sentinel node biopsy performed in the neoadjuvant setting for breast cancer: results from the I-SPY TRIAL (CALGB 150007/150012 & ACRIN 6657).
Authors: Gomez RE , Zakhireh J , Moore D , DeMichele A , Przewoznik J , Ollila D , Frank J , Krontiras H , Montgomery L , Sarode V , Broadwater G , Esserman L , Network the I-SPY TRIAL
Published: December 2010

Abstract #202

Introduction: Controversy remains over whether to perform sentinel node biopsy (SNB) before or after neoadjuvant chemotherapy (NAC). We examined the practice patterns, feasibility, and accuracy of this procedure in high risk breast cancer patients treated with NAC in a multi-institutional correlative science study.  Methods: Patients with biopsy-proven breast cancer >3 cm enrolled into the I-SPY TRIAL to undergo 4 weeks of anthracycline-based NAC, 4 weeks of taxane treatment, then surgical intervention. Study protocol did not dictate axillary treatment. Timing of SNB was dictated by the surgeon. Practice patterns, outcome of SNB and axillary lymph node dissection (ALND), locoregional recurrence and distant metastases were recorded with a mean follow-up of 2.9 years.  Results: 237 patients enrolled, 221 completed the trial, 210 had complete data at the time of analysis; Table 1 shows axillary practice patterns.    Overall, 43% had a positive SNB and/or ALND after NAC. 129 (61% of 210) patients presented with clinically positive nodes, 39 of which had a post-NAC SNB. 5/39 had no ALND (all SNB negative). Table 2 shows results for those who had a post-NAC SNB and ALND. For this subset of patients, sentinel node ID, accuracy, and false negative (FN) rates were 80%, 91% and 15% respectively. If SNB was negative, 20% of patients still had a positive ALND. 81 (39% of 210) patients presented with clinically negative nodes, 22 of which had a post-NAC SNB. 8/22 post-NAC SNB patients had no ALND (6 negative, 2 positive for 1mm disease). Table 2 shows results for those who had a post-NAC SNB and ALND. For this subset of patients, sentinel node ID, accuracy, and FN rates were 100%, 100% and 0%.    Overall, there were 26 deaths; 96% occurred in those who presented with clinically positive nodes, 77% had positive post-NAC nodes. A negative axilla post-NAC was predictive of longer DFS over those with axillary disease post-NAC (p<0.05).  Conclusions: In clinically node negative patients, post-NAC SNB is feasible and accurate before or after NAC. Our data suggests that a post-NAC SNB is sufficient; this avoids an additional operation and allows us to gain information on post-NAC axillary status which is of prognostic significance. In clinically positive patients, SNB does not adequately reflect axillary disease; even when SNB was negative, 20% still had axillary disease. At this time, we recommend that ALND be performed on all clinically node positive patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 202.
Chromosome translocations and fusion genes in breast cancer.
Authors: Howarth KD , Batty EM , Beavis JC , Blood KA , Newman S , Ng B , Pole JC , Chua Y , Ichimura K , Collins VP , Project CG , Chin S , Caldas C , Carter NP , Edwards PA
Published: December 2010

Abstract #2021

Background: Little is known about chromosome translocations in the common epithelial cancers such as breast cancer, in spite of the central role played by translocations and consequent gene fusions in haematopoietic cancers.  Methods: We present a comprehensive analysis by array painting of the chromosome translocations of four breast cancer cell lines, DU4475, HCC1806, HCC1187 and ZR-75-30. In array painting chromosomes are isolated by flow cytometry, amplified and hybridized to DNA microarrays. All breakpoints, totalling nearly 250, were mapped to at least 1Mb resolution and most balanced breakpoints were mapped to about 2kb resolution using custom oligonucleotide arrays. The remaining unbalanced breakpoints were mapped to around 20kb by identifying copy number steps in Affymetrix SNP6 array hybrizations obtained by the Sanger Institute's Cancer Genome Project. Breast tumours in parraffin section in tissue microarrays were screened by FISH to see whether selected breakpoints found in the cell lines are present in breast tumours.  Results: We found at least 12 reciprocal translocations in the four cell lines, substantially more than expected, and many more rearrangements were balanced for at least one participating chromosome. Many of the breakpoints were within or adjacent to cancer-relevant genes, and three of the translocations have already been shown to form fusion transcripts, RIF1-PKD1L1, PUM1-TRERF1 and TAX1BP1-AHCY. For selected genes targetted by the translocations, about 100 breast tumours were screened for breaks. Breaks were found in two to six cases for several of the genes, confirming that some of them were broken in breast tumours. For example two cases of unbalanced breakage were identified in PKD1L1, and these were confirmed by array-CGH.  Discussion: Our results suggest that breast cancers have fusion genes, and support the emerging view that chromosome rearrangements are likely to play a significant role in common epithelial cancers.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2021.
The pattern of metastatic spread among breast cancer sub-types.
Authors: Kennecke HF , Yerushalmi R , Woods R , Cheang M , Voduc D , Speers C , Nielsen T , Gelmon K
Published: December 2010

Abstract #2025

Background: Although breast cancer subtypes are associated with differing relapse risks, the patterns of metastatic spread are less well defined, particularly for more than the first site of metastasis. We describe the sites of all diagnosed metastases among breast cancer subtypes in a large series of women diagnosed with breast cancer to further define patterns of spread.  Methods: Subjects with early stage breast cancer referred to the British Columbia Cancer Agency from 1986 to 1992 were included. Archival paraffin tissue blocks were used to construct a tissue microarray. Breast cancer subtypes were defined as Luminal A (ER/PR+ and HER2- and Ki67 <19%), Luminal B (ER/PR+, and HER2- and Ki67 >19%), LuminalHer2 (Her2+ and ER/PR+), HER2 (HER2+ and ER- and PR-), and Basal (HER2-ER-PR- and CK 5/6+and/orEGFR+). All documented sites of distant metastasis were abstracted by chart review according to predefined categories.  Results: 3526 eligible women were classified according to Luminal A (2109), Luminal B (514), LuminalHER2 (252), HER2 (276) and Basal (375) and 30%,47%, 48%, 50% and 42% in each subgroup were diagnosed with distant metastasis. Median Survival with metastatic disease was 2.2, 1.6 and 1.3 years in Luminal A, B and LuminalHER2 groups and 0.7 and 0.5 years in the HER2 and Basal types, respectively. Bone was the predominant site of metastasis for luminal groups A (76%), B (73%) and LuminalHER2 (70%). The distribution was more heterogeneous in HER and Basal groups. High rates of brain metastasis were observed in the HER2 (30%) and Basal (27%) and less frequently in the LuminalHER2 (17%) and other groups (p <0001).    Conclusion: Molecular breast cancer subtypes are associated with specific distributions of metastasis which may lead to specific prophylactic therapies to modify this risk. New systemic therapies, including trastuzumab, may impact these patterns and survival after recurrence.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2025.
A comprehensive analysis of nine prognostic signatures reveals the high classification instability in breast cancer.
Authors: Reyal F , Vliet MH , Horlings HH , Armstrong N , de Visser KE , Kok M , Teschendorff AE , Mook S , Van't Veer L , Caldas C , Salmon RJ , Van de Vijver MJ , Wessels LF
Published: December 2010

Abstract #2026

To determine the prognosis of breast cancer patients, clinical and pathological factors are currently employed. Gene expression micro-arrays offer new opportunities to determine individual prognosis. Publications have raised concerns about micro-arrays studies who have the potential to preclude their use in clinical routine. To improve the understanding of gene-expression classifiers we addressed the following issues: 1) Is the performance similar between independent classifiers? 2) Is proliferation a common biological theme that represents various signatures? 3) Are there other enriched pathways among signatures with prognostic ability?  Methods:  On 6 public datasets we applied the 76-gene signature; the Molecular subtypes; the Chromosomal Instability Signature; the Wound Signature; the Invasiveness Gene Signature; the Molecular Prognosis Index; and the Genomic Grade Index. Survival, predictive accuracy and overlap analyses were performed. We created enlarged signatures by including all probes with significant correlation to at least one of the genes in the original signatures. We gathered a collection of gene sets from four databases (GO, KEGG, Reactome, MSDB). For each signature, we evaluated whether specific gene sets (modules) are overrepresented. We tested the prognosis ability of each of them.  Results:  The survival and predictive accuracy analyses gave similar results for each of the 9 signatures. They all added significant information to a multivariate model including standard pathological and clinical criteria. Nevertheless, we showed that none of these signatures were able to identify good and poor prognosis patients when applied to samples with intrinsically poor prognosis features (Positive Lymph Node, Negative Estrogen Receptor, High Grade). Conversely they identified good and poor prognosis patients when applied to samples with intrinsically good prognosis features (Negative LN, Positive ER Low Grade). The overlap analysis showed a low agreement between the signatures. 50% of the samples had almost one discordant classification result out of the 9 classifiers tested. The intersection of the signatures revealed a set of proliferation genes. The signatures were build on 10 different gene ontology modules with prognostic ability.  Conclusion:  This study underlines the need of large prospective validation studies of gene expression signatures. Further computational intelligence and system biology studies would be held to determine the best way to use these classifiers in clinical routine.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2026.