bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of a home-based physical activity intervention upon exercise behaviors and anthropometric measures in women undergoing treatment for early stage breast cancer.
Authors: Ligibel JA , Campbell N , Anita G , Shockro L , Salinardi T , Winer EP
Published: December 2010

Abstract #1117

Women who gain weight after breast cancer diagnosis have a worse prognosis compared to women who avoid weight gain. Weight gain is especially common in women treated with adjuvant chemotherapy, many of whom develop sarcopenic obesity which involves an increase in body fat and loss of lean muscle mass. This type of weight gain has been associated with increases in insulin and other metabolic hormones linked to breast cancer risk and prognosis. Studies have demonstrated that weight gain in breast cancer patients occurs, at least in part, due to decreases in physical activity during and after treatment.  Methods: In this single arm pilot study, sedentary women with early stage breast cancer participated in a home-based exercise intervention during adjuvant chemotherapy and/or radiation. The target activity goal was 150 minutes of aerobic exercise per week. Participants underwent evaluation of anthropometric measures, fitness (measured by modified Bruce ramp protocol treadmill test), fatigue and quality of life at baseline and after the 12 week intervention. Change in these measures over time was assessed using Wilcoxon signed rank test of the change scores (post-pre values).  Results: Forty-one women were enrolled in the study and 33 (80%) completed the 12 week protocol. Average age of participants was 47, and women were an average of 4.5 months from diagnosis at the time of enrollment. All but one of the women (98%) received adjuvant or neoadjuvant chemotherapy. Baseline and week 12 values for study variables are presented in table 1. Participants were sedentary at baseline, engaging in an average of 13 minutes of weekly activity. Physical activity increased significantly during the study period, with participants averaging 105 minutes of activity per week. Participants avoided weight gain and increases in body fat over the course of the study, and experienced significant improvements in fitness, quality of life and fatigue scores.    Discussion: Women who completed a 12-week home-based exercise intervention during adjuvant therapy significantly increased activity and avoided weight gain, which has been associated with poor prognosis in early stage breast cancer. This trial, in conjunction with other exercise studies in breast cancer patients, provides preliminary data to help guide the design of randomized trials examining the impact of exercise upon breast cancer outcomes.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1117.
Onset and risk factors for aromatase inhibitor-related arthralgia in breast cancer survivors.
Authors: Mao JJ , Stricker CT , Bruner DW , Farrar JT , Bowman MA , Xie SX , Wolf J , DeMichele A
Published: December 2010

Abstract #1120

Purpose: Arthralgia is a common clinical phenomenon seen in postmenopausal women receiving aromatase inhibitors (AI). This study aims to evaluate the perceived onset, prevalence, and risk factors for AI-related arthralgia.  Patients and Methods: We performed a cross-sectional analysis of a cohort of postmenopausal women with stage I-III breast cancer receiving adjuvant AI therapy at an outpatient breast oncology clinic at a large university hospital. Patient-reported symptoms and attribution of AI as a cause of arthralgia were main outcomes. Multivariate logistic regression analyses were performed to assess risk factor(s).  Results: 300 patients have been enrolled, with a mean age of 61 +/- 10 years, 84% White, and 38(13%) Black. A total of 173 (58%) reported AI-related arhtralgia during the course of AI treatment and 139 (47%) attributed AI as a cause of their current arthralgia. While 103 (34%) reported having “arthritis” prior to AI initiation, 13% reported onset of symptoms within 1 month of medication initiation, 42% between 1-3 months, 27% between 3-6 months, 12% between 6-12 months, and 20% after 12 months. In a multivariate logistic regression model, time since last menstrual period (LMP) was the only significant predictor of reporting AI-related arthralgia; age, race, employment status, chemotherapy, and weight gain since breast cancer were not associated with the clinical syndrome. Controlling for these covariates, those who had LMP within 5 years had the highest probability of reporting AI-related arthralgia (73%), while those with LMP beyond 10 years had the lowest (35%), p=0.017. Prior arthritis was unrelated to AI-related arthralgia either in univariate or multivariate analyses.  Conclusions: AI-related arthralgia is common and appears to be inversely related to the length of time since cessation of menstrual function. These findings suggest that estrogen withdrawal may compound these symptoms and may play a role in the mechanism of this disorder.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1120.
Reversal of skeletal effects of endocrine treatments in the intergroup exemestane study.
Authors: Coleman RE , Banks LM , Girgis S , Vrdoljak E , Fox J , Cawthorn S , Patel A , Coombes C , Bliss JM , Kilburn LS , Group on Behalf of the IES
Published: December 2010

Abstract #1128

The Intergroup Exemestane Study (IES) has demonstrated significantly improved disease related outcomes for post-menopausal women with ER+/unknown early breast cancer who switch to exemestane (E) after 2-3 years pre-treatment with tamoxifen (T). In comparison to 5 years T, a switch to E is associated with a favorable adverse event profile other than an increase in musculoskeletal side effects, accelerated bone loss & increased fracture incidence. Here we report effects of endocrine treatment withdrawal on bone mineral density (BMD) at lumbar spine (LS) & total hip (TH), bone turnover markers (BTM) & fracture rates.  Of the 4724 patients (pts) who took part in IES, 206pts (101E, 105T) at selected centres with no evidence of osteoporosis or osteoporotic fracture were included in a bone health substudy. BMD & BTM were assessed pre-randomization, after 6, 12, & 24 months (m) treatment, end of treatment (EOT), 12 & 24m post EOT. BTM were also assessed after 3, 9, 18, 30 & 3m post EOT. To evaluate treatment withdrawal effects, 12 & 24m post EOT BMD results are available for 160 (76E, 84T) & 159 (75E, 84T) pts respectively. Similar pt numbers also had BTM (urinary NTX & DPD, serum CTX, bone ALP, osteocalcin & PICP) measured post EOT.  At EOT an ITT analysis showed that the switch to E was associated with a -3.9% & -3.0% reduction since randomization in LS & TH BMD respectively, compared with -1.2% &-1.6% for continuing on T, resulting in an EOT difference between mean E & T BMD of 2.8% (p=<.0001) & 1.4% (p=.002). Following treatment withdrawal this difference was partially reversed. LS & TH BMD increased after E by 1.7% & 0.3% & fell by 2.2% & 2.8% with T at 24m from EOT. At 2 years post EOT there were no significant differences in BMD between treatment strategies.    Corresponding changes in BTM were seen with an increase following T withdrawal & a reduction in previously E induced acceleration of bone turnover. In IES main study a higher number of fractures were seen in E pts after a median follow-up of 74m; further analyses will describe changing pattern of events over time. The adverse effects of E on bone are partially reversed on treatment withdrawal while beneficial effects of T are lost during the 2 years after EOT.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1128.
Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with early breast cancer: results from the TEAM trial neuropsychological side study.
Authors: Schilder CM , Seynaeve C , Linn SC , Boogerd W , Beex LV , Gundy CM , Huizenga HM , Nortier JW , v/d Velde CJ , van Dam FS , Schagen SB
Published: December 2010

Abstract #1133

Background  Adjuvant hormonal therapies (HT) are frequently used in primary breast cancer (BC), yet few studies have examined their potential impact on cognition. Fundamental and human research indicate that estrogens play an important role in certain cognitive functions; therefore it is plausible that HT can affect cognition in BC patients (pts). Due to different mechanisms of action, distinctive effects between selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) are possible.  Methods  Neuropsychological examinations were used to study cognitive performance before the start of adjuvant HT (T1) and after one year of HT (T2) in postmenopausal BC pts not qualified to receive chemotherapy. Study pts participated in the Dutch part of the international TEAM-trial, a prospective randomized study investigating tamoxifen (SERM) versus exemestane (AI) as adjuvant therapy for hormone-sensitive BC. The study sample consisted of 80 tamoxifen users (mean age 68.7 yrs, range 51-84) and 99 exemestane users (mean age 68.3 yrs, range 50-82). A healthy control group (n=120, mean age 66.2 yrs; range 49-86) was assessed with a similar interval. Differences in performance at T2 on 8 cognitive domains were studied among the three groups by use of ANCOVA twice: (1) adjusting for performance at T1 and (2) with additional adjustment for the covariates anxiety/depression, fatigue and menopausal symptoms at T2.  Results  After one year of therapy, exemestane users did not perform significantly worse than healthy controls on any cognitive domain. Tamoxifen users performed worse than healthy controls on 'verbal memory' (P=.003, Cohen's d = .43) and 'executive functioning' (P=.005, Cohen's d = .40) and worse than exemestane users on 'information processing speed' (P=.019, Cohen's d = .36). Adjustment for covariates did not change these results. For 'visual memory', 'working memory', 'verbal fluency', 'reaction speed' and 'motor speed' no significant differences between groups were found.  Discussion  After one year of therapy, tamoxifen has a negative impact on certain cognitive functions, while exemestane does not negatively affect cognition in this population. Although the burden of these effects on the daily life of pts has yet to be determined, intact cognition is known to be an important precondition for independent living and wellbeing. Currently, the options of HT in BC are increasing and optimization of HT with respect to the choice, sequence and duration of treatments is given high research priority. Our results underscore the need to include cognitive effects of HT in long-term safety studies.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1133.
Bone effects of exemestane vs. tamoxifen within the TEAM trial: results of a prospective randomized bone sub study.
Authors: Hadji P , Ziller M , Kieback D , Dornoff W , Tessen HW , Kuck J , Hasenburg A
Published: December 2010

Abstract #1143

Background: A prospective open label randomized multicenter trial was performed in the German TEAM Trial Group to compare the effects of the steroidal aromatase inhibitor Exemestane (EXE) and the ER agonist/antagonist Tamoxifen (TAM) on bone mineral density (BMD) and markers of bone turnover during adjuvant treatment of postmenopausal women with estrogen receptor positive breast cancer.  Methods: 200 postmenopausal estrogen receptor positive breast cancer women  were included in the bone substudy. Women with a history of osteoporosis or a disease or treatment known to effect bone metabolism were excluded. BMD and markers of bone turnover were assessed at baseline, after 6 and 12 months of treatment. BMD was performed using dual x-ray absorptiometry (DXA) at the lumber spine and femoral neck (FN). Marker of bone formation, PINP, bone specific alkaline phosphatase (BAP) and osteocalcin (OC) as well as bone resorption marker (ICPM) were analysed using standardised methods. Intent-to-treat analysis was performed based on 200 patients. The primary endpoint was to compare Exemestane and Tamoxifen with regard to changes from baseline to month 12 in BMD (g/cm²) in lumbar spine (integral of L1-L4). Results: 156 patients with a mean age of 61 yr. (+/- 7.3 yr.) were available for final analysis. Both groups were comparable regarding age, height, tumor grade and stage. Compared to women on Tamoxifen, who comprised an BMD increase of +0.9% and +0.9% after 6 and 12 months at the spine, women on EXE showed a decrease of -2.8% and -3.6%. Conversely, BMD at the FN showed a decrease of -2.1% and -2.2% in women on TAM while women on EXE showed a decrease of -3.4% after 6 and an increase of +1.1% after 12 months, respectivly. Bone formation and absorption was modulated in both groups. Details will be presented at the meeting.Conclusion: The results of the 12 months analysis in the TEAM Bone substudy confirm the bone protective effect of TAM at the spine while conversely the results at the FN showed a decrease. Women on EXE showed a decrease at the spine while there was a neutral effect at the FN. Futher evaluation of the 24 months data as well as the fracture rate of the total TEAM trial are nessecary to evaluate the effect of EXE on bone health.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1143.
A global perspective on the use of aromatase inhibitors in early-stage breast cancer.
Authors: Jackisch C , Verma S
Published: December 2010

Abstract #1144

Background: Aromatase inhibitors (AIs) are considered to be the standard of care for the adjuvant treatment of postmenopausal patients with hormone-receptor positive (HR+) early breast cancer (EBC). However, there is a lack of data on the use of these drugs in the non-trial setting and in regional practice around the world.  Methods: This survey examined the use of endocrine therapies in breast cancer by physicians in 7 countries. From July 27 to October 8, 2007, 462 physicians in the United States, Germany, the United Kingdom, France, Spain, Italy, and Japan were surveyed, and information was collected via an internet Web site. Data included the physicians' reported activity during the last month, AI profiles, and patient profiles according to treatment stage.  Results: Surveyed were 381 oncologists, 14 gynecologists, 36 surgeons, and 31 mammary gland clinicians. Physician perceptions were similar to the actual patient data. Half of all women being treated for breast cancer were HR+ and postmenopausal (less in Japan: 38%), and almost all of those patients (80-95%) were receiving endocrine therapy for the adjuvant treatment of EBC. AIs were the most common hormone agents used in the initial adjuvant setting of postmenopausal women with HR+ EBC across all countries surveyed (55-93%; median 88%). An upfront AI strategy was the most common practice overall, particularly in Japan, the United States, and France (89%, 86%, and 86%, respectively). Initial tamoxifen therapy was used predominantly in Germany (36%), the United Kingdom (51%), and Italy (55%). However, in the United Kingdom and Germany, the intent in nearly half of these patients was to switch to an AI following 2 years of tamoxifen therapy. The rates at which the 3 AIs were prescribed for different types of adjuvant treatment were generally consistent across countries. Guidelines were identified as a major decision-making factor in all countries.  Conclusion: There are variations in practice across the surveyed countries despite the presence of international guidelines, eg, the American Society of Clinical Oncology and St. Gallen 2007. These practice trends may reflect the various guidelines in each region. Differences in treatment are particularly seen in Europe, which may reflect the number of varying guidelines and less descriptive nature of the guidelines.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1144.
Adriamycin and cyclophosphamide followed by tamoxifen, versus the combination of gonadotropin-releasing hormone analog and tamoxifen, in the treatment of premenopausal endocrine-responsive node-negative breast cancer.
Authors: Kim H , Lim W , Park E , Sei J , Koh B , Son B , Kim S , Ahn J , Gong G , Kim H , Jung K , Ahn S
Published: December 2010

Abstract #1151

Purpose  To compare the efficacy of adriamycin and cyclophosphamide (AC) followed by tamoxifen (AC->T) with gonadotropin-releasing hormone analog plus tamoxifen (GnRHa+T) in premenopausal women with hormone-response, node-negative breast cancer.  Patients and Methods   We retrospectively reviewed the records of 587 premenopausal women with hormone- responsive, node-negative breast cancer. Of these, 269 were treated with AC->T, and 318 were treated with GnRHa (goserelin acetate 3.6 mg/kg or leuprorelin acetate 3.75 mg/kg every 28 days subcutaneously)+T. The main study outcome was disease-free survival (DFS).  Results  At a median follow-up time of 30 months, eight patients had relapsed and three had died. DFS did not differ between the AC->T and GnRHa+T groups. Of the three deaths, two were not related to breast cancer. The third patient, in the AC ->T group, died because of brain metastasis. GnRHa+T treatment had no effect on blood profile and did not cause the development of detrimental symptoms but decreased bone mineral density. The efficacy of leuprorelin was similar to that of goserelin.  Conclusion   GnRHa +T and AC->T had comparable efficacy after 30 months of follow-up. The efficacy and tolerability of leuprorelin acetate was similar to that of goserelin.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1151.
Effect of exemestane on bone turnover markers and bone mineral density (BMD): 2 year results of the Dutch/Belgian Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial.
Authors: van Nes JG , Papapoulos SE , Braun JJ , Dirix L , Putter H , Zwaan RE , Ballieux BE , van Rongen I , van de Velde CJ , Seynaeve C , Nortier JW
Published: December 2010

Abstract #1154

Background Aromatase inhibitors (AIs) given to women with early breast cancer may adversely affect bone metabolism. We studied the effect of exemestane (E) on bone mineral density (BMD) and bone turnover and compared it to the effect of tamoxifen (T) treatment in a group of women participating in the Dutch and Belgian Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial. In this trial, postmenopausal women with hormone sensitive early breast cancer (n=3168) were randomised between 5 years E or 2½-3 years T followed by 2½-2 years of E.  Methods In this subprotocol, 87 women were followed for two years. Patients with bone diseases were excluded. Total hip and lumbar spine BMD were assessed at baseline and after 1 and 2 years. The bone resorption marker cross-linked telopeptide of type-I collagen (CTX) and the bone formation marker N-terminal propeptide of type I collagen (PINP) were measured in fasting serum at baseline and after 3, 6, 12 and 24 months.  Results At baseline, there was no difference in total hip (E: 0.85g/cm2, T: 0.80g/cm2; p=0.642) and lumbar spine BMD (E: 0.99g/cm2, T: 1.02g/cm2; p=0.545) between both groups. After 2 years, there were no significant changes in total hip BMD (E: 0.02 g/cm2 95%CI -0.05;0.08, p=0.849; T: 0.03 g/cm2, 95%CI -0.02;0.09, p=0.466) and in spine BMD (E: -0.02 g/cm2 95%CI -0.11;0.06, p=0.834; T: 0.02 g/cm2 95%CI -0.05;0.10, p=0.747). At baseline, there was no difference in serum CTX (E: 0.34ng/mL, T: 0.29ng/mL; p=0.271) and P1NP (E: 57ng/L, T:58ng/L, p=0.973) between both groups. After 2 years of treatment, serum CTX increased, although not significantly in the E group (20%, 95%CI -6%;54%, p=0.223) while it decreased significantly in the T group (-40%, 95%CI -23%;-53%, p<0.001). At 24 months, the CTX was 0. 44ng/mL (E) and 0. 18ng/mL (T). Serum P1NP did not change in the E group (-2%, 95%CI -20%;19%, p=0.837) but decreased significantly in the T group (-48%, 95%CI -36%;-58%, p<0.001). At 24 months, the P1NP was 55ng/L (E) and 28ng (T).  Conclusion Although there was a trend for an increase in bone resorption with E treatment, this was not significant and was not associated with a decrease in BMD. The magnitude of the reported negative effect of aromatase inhibitors on bone metabolism in studies using T as comparator treatment may be overestimated by the effect of T on bone turnover.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1154.
Local control with conventional and hypofractionated adjuvant radiotherapy for ductal carcinoma in-situ: is there a difference in outcome?.
Authors: Williamson D , Fung S , Pintilie M , Dinniwell R , Fyles A
Published: December 2010

Abstract #1162

Purpose  Trials of adjuvant whole breast radiotherapy (WBRT) following breast-conserving surgery for invasive breast cancer indicate equivalent efficacy and morbidity for conventional and hypofractionated treatment. WBRT for ductal carcinoma in-situ (DCIS) improves local control, however an optimal dose fractionation remains undefined. Our group policy allowed for the use of both schedules, therefore we compared local control in women with DCIS following breast-conserving surgery.  Methods  Two hundred and sixty six patients treated between January 1999 and December 2004 with conventional (50 Gy/25 fractions) or hypofractionated (42.4 Gy/16 daily fractions or 40 Gy/16 fractions + 12.5 Gy/5 fraction boost) radiotherapy schedules to the whole breast after breast-conserving surgery for DCIS were identified and retrospectively reviewed. Treatment schedules were evaluated for outcomes in terms of ipsilateral breast recurrence.  Results  The median age at diagnosis 56.7 years (range 32.2-83.8 years), and 82% (218 patients) presented with mammographic abnormality. Median tumour size was 1.5 cm (range 0.4-10 cm), grade 3 tumours were present in 105 women (39%), and comedonecrosis in 145 (55%). Fifty-one patients (19%) had multifocal disease. Median follow-up was 45.1 months (range 0.7-106.8 months). Prognostic features were well matched in both groups.  One-hundred and four patients (39%) were treated with conventional and 162 (61%) with hypofractionated WBRT. There were a total of 14 confirmed local recurrences in the previously radiated breast. Six recurrences occurred in the 104 (5.8%) patients treated with a conventional schedule and 8 of 162 (4.9%) patients treated with a hypofractionated schedule. Actuarial risk of recurrence at 4 years was 7% with hypofractionated WBRT and 5% with a standard schedule (p=0.85).    Eight patients recurred with DCIS and 6 with invasive carcinomas, all 14 were treated surgically with adjuvant treatment as indicated clinically, 1 patient with clinical recurrent disease refused biopsy and further conventional treatment. Univariate analysis showed a trend to increased risk of recurrence with grade 3 tumours (10% at 4 years vs. 3% for grade1/2, p=0.053) and presence of comedonecrosis (8% vs. 2%, p=0.096), but not multi-focal disease (7% vs. 5%, p=0.78).  Conclusions  Hypofractionated adjuvant WBRT schedules following breast-conserving surgery for DCIS have comparable local control rates to a conventional radiation schedule. Hypofractionated WBRT is more convenient for patients, has equivalent morbidity and should be considered in this patient group.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1162.
Evaluation of preoperative letrozole treatment to DCIS by MRMammography.
Authors: Kuwayama T , Nakamura S , Yoshida A , Yagata H , Tsugawa K , Takei J , Tsunoda-Shimizu H , Suzuki K
Published: December 2010

Abstract #1164

Background:  Since ductal carcinoma in situ (DCIS) often spreads diffusely along a lactiferous duct as multicentric lesions, it is generally treated by mastectomy. The response rate to letrozole is approximately 60%, which is relatively high among the preoperative endocrine therapies for invasive cancer, and it enables at least 50% of patients with little chance of saving the breast to actually receive breast-conserving surgery. This study was conducted to determine the value of preoperative endocrine therapy with letrozole for postmenopausal patients with hormone receptor (HR)-positive DCIS.  Methods:  Postmenopausal women who had been diagnosed with HR-positive DCIS by needle biopsy (Allred score ≥3) were treated with letrozole for 12 weeks. The primary endpoint was the response of target lesions evaluated by MRI based on the RECIST criteria. Patients who had no safety problems, except PD, continued letrozole therapy for up to 24 weeks, and the tumor response after 24 weeks and the rate of breast-conserving surgery were assessed. In addition to RECIST-based evaluation, changes of tumor volume on MRI were examined. Changes of Ki67, bcl-2, ER, and PgR with letrozole therapy were also assessed.  Results:  Twelve postmenopausal women with DCIS were enrolled, but one patient was excluded because her Allred score was 2. Using by RECIST criteria , the tumor response after 12 weeks was CR in 1 patient and SD in 10 patients. All 6 patients who could be evaluated after 24 weeks showed SD. But the evaluation by tumor volumetoric method, tumor was significantly reduced to an average of 42.2% after 12 weeks compared to before treatment.(p=0.0057) Two patients continued letrozole therapy for longer than 24 weeks. After 24 weeks of therapy, 3 patients underwent breast-conserving surgery and no mastectomies were performed. Pathological findings showed that the spread of tumor was likely to that of preoperative MRMammogrraphy. PgR was significantly reduced by letrozole therapy. There were no safety problems was not observed.  Discussion:  The efficacy of preoperative treatment with letrozole for 12 weeks was verified in postmenopausal patients with HR-positive DCIS. Two patients received breast-conserving surgery after letrozole therapy that had been considered impossible before treatment. Evaluation of treatment to DCIS using by RECIST criteria is unsutable,but the evaluation by MRMammography is considered to be a suitable method for determining the efficacy of therapy for DCIS.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1164.
Using mathematical models to understand the time dependence of the growth of ductal carcinoma in situ.
Authors: Edgerton ME , Chuang Y , Macklin PT , Sanga S , Kim J , Tamaiuolo G , Yang W , Broom A , Do K , Cristini V
Published: December 2010

Abstract #1165

Background: Models of cancer growth have been developed that predict tumor size and growth dynamics for invasive tumors. However, it has been difficult to model ductal carcinoma in situ (DCIS) because of the constraints introduced by its containment within the duct system.  Materials and Methods: We have developed a spherical model of growth of solid type DCIS using chemical engineering models of reaction and diffusion in porous media to represent the spread of DCIS in the duct systems. The model predicts tumor diameter based on four input parameters: the ratio of the apoptosis rate to the proliferation rate (A), the diffusion penetration length for nutrient to sustain the tumor growth (L), the volume fraction that tumor cells occupied within the involved breast tissue (V), and the time taken for a cell to complete mitosis(T). We have estimated L, V, and T from the literature, and then back-calcuated A for a range of diameters. We have used these four parameters as inputs and studied the time dependence of the evolution of DCIS.  Results: We have found that the range of the values of A that we determined are within an adeqaute physiological range based on rates of proliferation and apoptosis taken from the literature. Using the model, the time to reach at least 95% of the maximum size ranges from less than 30 days for DCIS measuring 0.5 cm to almost 80 days for DCIS measuring 6 cm in diameter.    Discussion: There has been little understanding of how long it takes for DCIS to grow, and whether it reaches a steady state size. Our simulations show that DCIS can grow to sizes as large as 6 cm in less than 3 months if it has the correct properties, including a high proliferation rate relative to the apoptosis rate and appropriate access to nutrients. This finding may help to explain why many cases of DCIS are not diagnosed before they progress to invasive carcinoma.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1165.
CA 27.29 as a tumour marker for risk evaluation and therapy monitoring in patients with primary breast cancer.
Authors: Hepp PG , Rack BK , Mouarrawy D , Groh U , Graf H , Göhler T , Finas D , Hönig A , Lichtenegger W , Sommer H , Janni W
Published: December 2010

Abstract #2004

Background:  Several trials show that the use of tumor markers leads to an early diagnosis of tumor dissemination in breast cancer patients. Whether this improves the prognosis is still under discussion. In the SUCCESS Trial CA27.29 has been examined before and after adjuvant chemotherapy (n=3754).  Methods:  The SUCCESS Trial compares FEC-Docetaxel (Doc) vs. FEC-Doc-Gemcitabine (Doc-G) regime and two vs. five year treatment with Zoledronat in patients with primary breast cancer (N+ or high risk). CA27.29 has been measured with ST AIA-PACK Ca27.29 reagent using MUC-1 for AIA-600II (Tosoh Bioscience, Tessenderlo, Belgium). The cutoff for positivity of CA27.29 is 24 U/ml.  Results:  2669 patients have been examined prospectively before and after chemotherapy. 22% of patients had a marker >24 U/ml (n=587, mean 19.00, range 3.04-410.00) before and 40% (n=1058, mean 23.34, range 2.70-330.76) after chemotherapy. The correlation between both values was significant (p<0.0005).  While 17% showed elevated CA27.29 before and after therapy, 5% patients changed from positive to negative for CA27.29 afterwards. 55% were negative before and after therapy whereas 23% became positive after treatment.    Before treatment the prevalence of elevated CA27.29 was equally distributed between the FEC-Doc and the FEC-Doc-G arm. After treatment 34.1% in the FEC-Doc arm showed an increased level vs. 45.6% in the FEC-Doc-G arm. The correlation analysis showed no significant coherence between hormonal status (ER: p<0.323; PR: p<0.078), HER2/neu status (p<0.308), Grading (p<0.565) and CA27.29 level. However, tumor size (p<0.020) and the nodal status (p<0.022) were significant associated with Ca27.29 levels.  Conclusion:  These results might indicate a close relation between Ca27.29 and tumour mass at primary diagnosis. Whether this marker will be useful for treatment monitoring will be shown by further follow-up in the Success-trial.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2004.
HoxC6 regulation of early mammary epithelial growth and differentiation: implications for breast cancer potential.
Authors: Zhang G , Neumann CA , Moreno CS , Rosenzweig SA , Spyropoulos DD
Published: December 2010

Abstract #2010

Background: Early menarche and breast development are increasingly common risk factors for breast cancer. Epigenetic mechanisms implicated include natural and anthropogenic steroids, such as estrogens, that disrupt endocrine signaling and dysregulate stem cell homeostasis. Animal models show that, although a proliferative response to estrogens in mammary epithelium is not observed until near puberty, in utero or neonatal exposure can recapitulate aberrant breast development. The molecular basis for the delay in proliferative response remains poorly understood and assessments of agent activity, potency and risk remain inaccurate. Here, we provide a candidate molecular mechanism involving the homeobox transcription factor HoxC6, through which more accurate assessments may be facilitated.  Materials & Methods: Genetically and hormonally manipulated in vivo mouse models (HoxC6 targeted disruption, C6KO; and mammary epithelial-specific inducible HoxC6, MMTV-rtTA TRE-HoxC6-IRES-EGFP) and in vitro human breast cancer cell lines (MCF10A, MCF7 and MDA-MB-231; "231") were used to assess impacts on mammary epithelial growth, differentiation and expression of HoxC6 and its direct target genes IGFBP3, CD44 and FGFR2. Cell lines were manipulated using HoxC6 shRNA and cDNA lentivirus and activated Akt isoform retroviral expression vectors. Gene expression and signaling were measured by quantitative RT-qPCR, IHC, Western blot and using the BioPlex200 Multiplex System.  Results: RT-qPCR analysis shows HoxC6 expression elevated in well-differentiated cell lines (MCF10A, 5.06X; MCF7, 5.16X) and decreased in more aggressive tumor cell lines (-1.95X, 231 cells; relative to A549 cells). HoxC6 knockdown in MCF10A cells results in an inhibition of cellular growth and decreased branching in 3D cultures and dysregulation of HoxC6 target genes. These results are consistent with in vivo results in which C6KO causes defective postnatal mammary epithelial growth/branching. Rescue of growth defects in knockdown MCF10A cells is achieved to varying extents with myristoylated Akt isoforms, however morphological defects persist and are associated with EMT. HoxC6 induction in stem cells is associated with altered self-renewal and differentiation. HoxC6 repression by estrogens was assessed in vivo under conditions of neonatal estrogen exposure and estrogen-free diets, showing alterations in HoxC6 and target gene expressions and other phenotypic changes.  Discussion: Based on our results, we will present a model in which HoxC6 is estrogen-responsive and coordinates mammary stem/progenitor cell homeostatic pathways, including FGF and GH-IGF1 signaling in the control of pool size and branching morphogenesis.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2010.
Heregulin induces Iressa-resistance of breast cancer cells through receptor heterodimerization.
Authors: Li J , Liu H , Espinoza I , Lupu R
Published: December 2010

Abstract #2016

Background: Heregulins (HRGs) are known as soluble secreted growth factors that are involved via binding and activating HER3 and HER4 cell surface receptors in cell proliferation, metastasis, survival, and differentiation in normal and malignant tissues. We have previously shown that up-regulation of HRG is sufficient for development of mammary tumors independently of estrogen stimulation and HER2 overexpression. Moreover, inhibition of HRG expression suppresses the aggressive phenotype by decreasing HER activation and reducing matrix metalloproteinase-9 activity. Therefore, HRG appears to be a key modulator of tumorigenicity and metastasis in triple negative breast carcinomas. Resistance to anti-epidermal growth factor receptor (anti-EGFR) therapies such as gefitinib is an emerging clinical problem. In this regard we have used MDA231, HS578T and BT549 cells to study potential mechanisms of gefitinib resistance. These cell lines are EGF independent and express high levels of HRG and resistant to gefitinib. Our hypothesis is that HRG signaling through HER3 induces resistance to EGFR blockade. To demonstrate this, we knocked down HRG expression by RNA interference (RNAi) in MDA231, HS578T, and BT549 cells.  Material and Methods: Down-regulation of HRG is observed in MDA231, HS578T, and BT549 cells transduced with HRG siRNA lentiviral vector pRNAt-U6.2. Sensitivity to gefitinib was determined by MTT assays and soft agar assays. Each experiment was repeated at least 3 times, all data were analyzed by ANOVA. The level of significance was set at p < 0.05.  Results: Our results show that when comparing to their parental cells, all MDA231/HRGsiRNA, HS578T/HRGsiRNA and BT549/HRGsiRNA cells grew at a lower rate and become sensitive to gefitinib. Our results indicate that HRG can overcome the inhibitory effects of gefitinib on cell growth and HRG signaling allows at least in part, the acquisition of gefitinib-resistant phenotype.  Discussion: Although the mechanism for the resistance is still under further investigation, our observation has implications for the effectiveness of anti-EGFR therapies in breast cancer where HRG induced receptor heterodimerization in EGFR-positive breast tumors.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2016.
High resolution representational oligonucleotide microarray analysis (ROMA) suggests that TOPO2 and HER2 co-amplification is uncommon in human breast cancer.
Authors: McArthur HL , Tan LK , Patil S , Wigler M , Hudis CA , Hicks J , Norton L
Published: December 2010

Abstract #2023

  Background  Clinical studies relating TOPO2A expression or amplification by FISH have yielded inconsistent results regarding prediction of benefit from various drug therapies, particularly in the setting of HER2 amplification by FISH. Because HER2 and TOPO2A are relatively small genes that are close to each other, and because the relevant commercially-available FISH probes hybridize to DNA sequences beyond the genes of interest, there is significant potential for false positive results. We therefore conducted an exploratory study comparing HER2 and TOPO2A amplification by ROMA and FISH.  Methods:  Forty-two archived formalin-fixed paraffin-embedded primary breast cancer specimens were pre-selected to contain 36 HER2 amplified and 6 HER2 non-amplified cases by FISH. These specimens were evaluated for HER2 and TOPO2A amplification by FISH at Memorial Sloan-Kettering Cancer Center and by ROMA at Cold Spring Harbor Laboratory in a double-blinded experiment. Two HER2 amplified by FISH specimens proved inevaluable for technical reasons. The results for the remaining 40 evaluable specimens were then compared.  Results:  Of the 40 evaluable specimens, the 6 cases selected as HER2 non-amplified by FISH were HER2 non-amplified by ROMA and TOPO2A non-amplified by both FISH and ROMA. Thirty-two specimens were HER2 amplified by both FISH and ROMA. Two specimens with HER2 FISH results of 2.2 and 2.4 did not demonstrate focal amplification by ROMA. Twenty-five (74%) of the 34 specimens with HER2 amplification by FISH were TOPO2A non-amplified by both FISH and ROMA (Table 1). However, only 2 (22%) of the 9 specimens with HER2 and TOPO2A co-amplification by FISH demonstrated TOPO2A amplification by ROMA.    Conclusions:  Our results suggest that by ROMA, the determination of HER2 status (amplified and non-amplified) and TOPO2A non-amplification by FISH is accurate. The absence of TOPO2A amplification in HER2 non-amplified breast cancer is consistent with published reports. We also confirmed the published frequency of HER2 and TOPO2A co-amplification by FISH. However, we found that co-amplification of HER2 and TOPO2A by ROMA is uncommon, which suggests that commercially-available FISH probes over-estimate the frequency of TOPO2A amplification in HER2 amplified cases. Studies evaluating the clinical implications of these findings are underway.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2023.
Phosphoproteomic study of breast cancer: quantitative analysis of SH2 binding proteins.
Authors: Machida K , Claffey KP , Thompson CM , Hong S , Shin D , Mayer BJ
Published: December 2010

Abstract #2034

Background: An important biological process involved in breast cancer cell is tyrosine phosphorylation. Particularly, two tyrosine kinases, Src and HER2, are over expressed in invasive breast cancer tissues and both are considered excellent prognostic markers and therapeutic targets. Since tyrosine kinases transduce downstream signals by phosphorylating substrate proteins, leading to cellular responses, we assume the status of tyrosine-phosphorylated proteins in tumors can also provide molecular markers for breast cancer. Recently we established a method termed SH2 profiling, in which a battery of Src Homology 2 (SH2) domains are used to profile proteomes based on interaction between SH2 domains and tyrosine phosphorylated proteins. In this study we developed a semi-automated method to quantify SH2 binding proteins on multiple blots, and explored the feasibility of SH2 binding patterns as potential molecular markers for breast cancer. Material and Methods: Protein lysates from 10 breast cancer patient tissues as well as cancer cell lines were prepared and loaded into multiple precast gels. Proteins were separated using a SDS-PAGE multigel apparatus and transferred onto nitrocellulose membranes. Blocked membranes were incubated with HRP-labeled GST-SH2 domain probes, and SH2 binding patterns were detected by chemiluminescence with a phosphorimager. To correct blot-to-blot variation, we produced a semi-automated imaging tool for multiple blots. SH2 binding proteins were individually quantified based on their molecular sizes on blots, and different breast cancer samples were compared using the SH2 binding profiles. Results and discussion: 1. We have developed a method to quantify and incorporate data from multiple protein blots, a task that is always challenging due to blot-to-blot variation. 2. Using the semi-automated quantitation approach, large numbers of SH2 binding proteins in breast cancer samples were analyzed. SH2 domains including Vav2 and Eat2 bound strongly to proteins even in HER-2 negative tumors suggesting activation of HER-2 independent tyrosine kinase signaling pathways in breast cancer. 3. Further development of the quantitation method is underway to determine if specific SH2 binding patterns are potential prognostic molecular markers for breast cancer. This study is supported by the Connecticut Breast Health Initiative, Inc.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2034.
Evaluation of CD83 antigen in the normal mammary epithelium and fibroadenoma human.
Authors: Borges MN , Silva ID , Silva BB , Araujo Neto JT , Facina G , Nazario AC
Published: December 2010

Abstract #2038

Background: The immune response initiation requests the capture and the presentation of the antigens to the specific lymphocytes. The cells that has this capacity are denominated antigen-presenting cells, and the dendritic cell (DC) is the one that has larger specialization degree for these functions. The DC maturation it is considered essential for the beginning of the immune response. The CD83 antigen is a co-stimulator, member of the immunoglobulin superfamily with 45Kd, and your expression is an important marker of the maturation of DC.  Objectives: To analyze the CD83 antigen expression in the human's breast fibroadenoma and in the adjacent breast tissue and to identify the clinical features that can influence this expression.  Material and Methods: It is a retrospective study where 29 histopathologic materials of breast fibroadenomas and the adjacent breast tissue, of 28 women in reproductive age, were analyzed. The immunohistochemistry method was used for analysis of the CD83 antigen expression and, subsequently, the cells were counted by light microscopy. A thousand epithelium cells of each case were analyzed (five hundred of the fibroadenoma and five hundred of the adjacent breast tissue) for statistical calculation of the expression or not of the antigen reaction in the cells. We used parametric test (t-Student) for statistical analysis of the results.  Results: The CD83 antigen expression positive in the fibroadenoma's cells (365.52 ± 133.13) in relation to the adjacent breast tissue's cells (189.59 ± 140.75) was statistically greater (p <0.001). Several clinical features were analyzed, however, only parity showed influence in the expression of the CD83 antigen in the adjacent mammary tissues, and the positive expression was more evident in nulliparous women (p=0.042).    Conclusion: The CD83 antigen expression was statistically greater in the breast fibroadenoma's cells, when compared with the one of the adjacent breast tissue. No clinical variable influenced CD83 expression in the breast's fibroadenoma, however, it was significantly greater in the adjacent normal breast tissue of nulliparous women.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2038.
Genomic and transcriptomic differences between lobular and luminal ductal invasive carcinoma.
Authors: Gruel N , Raynal V , Lucchesi C , Pierron G , Fourchotte V , Cottu P , Sastre-Garau X , Fourquet A , Delattre O , Vincent-Salomon A
Published: December 2010

Abstract #2039

Background: Invasive lobular carcinomas (ILCs) of the breast are characterized by morphological and phenotypical features such as small, non cohesive, estrogens receptors positive cells, low proliferation rates with a metastatic spreading in numerous and different unusual metastatic sites as compared to invasive ductal carcinomas (IDCs) (Ferlicot et al, 2004). We have previously shown that ILCs presented the same outcome than IDCs (Sastre-Garau et al, 1996). Beyond E-cadherin genomic inactivation, little is known about the underlying genomic and transcriptomic alterations that may discriminate both subtypes.  Aims of the study: To get an insight into ILC biological specificities, we performed a combined genomic (aCGH), transcriptomic (Affymetrix U133A+B) and phenotypic analysis of a series of 24 lobular carcinomas and compared it to a series of 41 ER-positive IDCs.  Results: Analysis of genomic copy number showed that ILCs and IDCs shared gains of the 1q11-q43 region and losses of 16q12.1-q24.2 and 17pter-p13.1 regions. ILCs presented the 22q12-q13 loss but not the 16pter-p11.2 gain and 11q23-q24 loss as observed in IDCs. Eight different regions of high level amplifications were found in 29% of ILC cases (7/24 cases). Only one region of amplification was recurrent and observed in 5 out of 24 tumors (21% of the cases). This recurrent region of amplification was localized on the 11q13.2 region and encompassed the Cyclin D1 (CCND1) and Cortactin (CTTN) genes. ILCs and IDCs had comparable overall survival rates, however, unsupervised hierarchical clustering of transcriptomic data showed that ILCs and IDCs clustered apart. Genes involved in cell adhesion and motility, lipid/fatty transport and metabolism and electron transport were differentially expressed between the two groups.  Conclusions: This integrated analysis emphasized the biological differences between ILC and IDC and highlighted genes of interest that could be useful for diagnosis, and could be new putative therapeutical targets.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2039.