bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-04-03: A Role for Cyclin D1 in Neoplastic Transformation in MCF-7 Breast Cancer Cells Post p14ARF-p53 Induced Senescence
Authors: McGowan E , Alling N , Shephard R , Yagoub D , Tran N , Xia P.
Published: April 2011

Many years of oncogenic insult and hormonal flux have important long-term implications for breast cancer emergence and progression. Premature-induced senescence is proposed to be a protective response against cancer development. We hypothesize that the senescence response can be subverted in some breast carcinomas, which exhibit latent hormone-dependent proliferative capacity.

The ARF-p53 pathway has long been known to play an important role in tumour surveillance halting cell cycle progression to transiently or permanently stop aberrant cells from proliferating. It is well documented that disruption of this pathway is involved in tumourigenesis, in part, through inactivation of cyclin D1. Cyclin D1 plays an important role in breast cancer progression as a regulator of CDK4/6. In addition cyclin D1 has been reported to stimulate estrogen receptor (ER) activity independent of CDK4/6.

Our initial observations showed that reactivation of ARF-p53-p21 is indeed a potent rapid inhibitor of cell proliferation in MCF-7 breast cancer cells with a senescent phenotype, however controversially cyclin D1 expression was increased and predominantly located in the nucleus. High expression of nuclear cyclin D1 and p14ARF inversely correlated with cell proliferation. Our studies showed that p14ARF regulated cyclin D1 at the post-transcriptional level. Furthermore, we have evidence from microRNA array analysis that microRNAs known to bind to the cyclin D1 3'UTR sequence were down regulated upon induction of p14ARF, contributing to cyclin D1 stability.

We found that long-term exposure to p14ARF was not a failsafe barrier to tumour progression, senescent-like cells re-entering the cell cycle correlated with reduction of nuclear cyclin D1. Conversely, continuous p14ARF expression resulted in chaotic multinucleation and preceded neoplasia. These aberrant nuclei co-stained with cyclin D1 and Ki-67, a well-known marker of cell proliferation.

These results suggest that induction of the p14ARF-p53 pathway does not entirely remove the threat of cancer resulting from hyperproliferative oncogenic signals and cyclin D1 plays a promiscuous role in prevention and progression. Arguably, in some breast cancers premature senescent cells may be precursor, or latent cancer cells.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-04-03.
Abstract P1-06-03: Chinese Herb Fructus Cornii Exhibits Preventive Efficacy in a Cell Culture Model for Hormone Responsive Breast Cancer
Authors: Telang NT , Sepkovic DW , Bradlow JL , Wong GYC.
Published: April 2011

Background: Selective estrogen receptor modulators and combination of chemotherapeutic agents represent conventional therapeutic interventional strategies for estrogen receptor positive (ER+) clinical breast cancer. Herbal medicines have been extensively used in alternative and complementary medicine for cancer of various organ sites. Concerns of adverse toxicity or acquired tumor resistance from conventional chemo-endocrine therapy, rationalizes the use of herbal medicines independently or in combination with chemo-endocrine therapy. The present study has utilized a human cell culture model for ER+ breast cancer to assess potential preventive efficacy of a popular Chinese nutritional herb Fructus Cornii (FC). Material and Methods: The ER+ human mammary carcinoma derived MCF-7 cells represented the model. Status of cellular metabolism of estradiol (E2), anchorage dependent growth and anchorage independent colony formation provided the quantitative end point biomarkers for efficacy.

Results: MCF-7 cells maintained in a serum depleted medium (E2<1 nM) retained E2 responsiveness as evidenced by growth modulation by E2, its metabolites, anti-estrogen Tamoxifen, and by the persistence of E2 metabolism via the C17-oxidation, C2-hydroxylation and C16α-hydroxylation pathways. Treatment of E2 stimulated MCF-7 cells with FC produced cytostatic growth arrest and reduction in the number of anchorage independent colonies in a dose dependent manner. Treatment of

MCF-7 cells with FC at the maximum cytostatic concentration increased anti-mitogenic 2-hydroxyestrone (2-OHE1), and decreased pro-mitogenic 16α-hydroxyestrone (16α-OHE1) formation.

Discussion: These data identify a mechanistic lead for the efficacy of FC and thereby, validate a human cell culture based approach for rapid prioritization of efficacious herbal medicinal products for prevention/therapy of ER+ clinical breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-06-03.
Abstract P1-07-02: Acceptability of Breast Cancer Medical Prevention by Letrozole in Post-Menopausal Women with a BRCA1/2 Mutation in the LIBER Trial
Authors: Pujol P , Mijonnet S , Dugast C , Berthet P , Lasset C , Fricker J-P , Delaloge S , This P , Baudry K , Nogues C , Martin A-L.
Published: April 2011

Background: Women carrying a germline BRCA1/2 mutation have a lifetime risk of developing breast cancer of 56 to 80%. Prophylactic bilateral mastectomy provides a valid option to reduce breast cancer incidence, but considerably affects the quality of life. There is therefore an urgent need to evaluate medical preventive alternative. The major breast cancer prevention trials using tamoxifen showed an approximately 50% incidence reduction in high risk women. Adjuvant trials comparing aromatase inhibitors (AI) to tamoxifen revealed a higher preventive efficacy of AI for contra-lateral cancer with fewer thrombo-embolic side effects.

Patients and Methods: The French federation of cancer centres (“FNCLCC”) has designed a randomized phase III trial to determine the efficacy of letrozole to prevent breast cancer in postmenopausal BRCA1/2 carriers. The “LIBER” study is a double-blind, letrozole versus placebo study involving 32 centers among with 20 are actives. The study opened for recruitment in march 2008.

Results: Here we present data reflecting the acceptability of this preventive trial. Twenty-one centers replied to an inquiry. 690 women were eligible. Out of 485 women informed by letter, 217 (44%) came to consultation and 62 (13%) entered the study. The main concerns of women while considering to enter the trial were: the potential side effects, the probability to receive the placebo and the lack of support from other practitioners. Out of 78 enrolled women, 48 (62%) were BRCA1 mutation carriers, 30 (38%) were BRCA2 mutation carriers, 73 (93%) were oophorectomized, 38 (49%) had a previous unilateral cancer, 40 (52%) did not have cancer. 30 (38%) women were less than 50 years old, and 48 (62%) were 50 or over 50 years old.

Discussion: For post-menopausal women bearing a BRCA1/2 genetic predisposition, prevention of breast cancer risk by letrozole could provide a precious alternative when bilateral mastectomy is not retained. Among women who received oral information, the acceptability of this randomized double-blind letrozole versus placebo trial is 28%.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-07-02.
Abstract P1-09-03: A Pharmaco-Economic Analysis of Tamoxifen (T) vs. Aromatase Inhibitors (AI) in Adjuvant Treatment of Postmenopausal (PoM) Women (W) with Hormone Receptor Positive (HRP) Breast Cancer (BC)
Authors: Sehgal R , Lark C
Published: April 2011

Background: Endocrine Therapy (ET) is an important component of adjuvant therapy in PoM W with HRP BC.AI are the preferred modality of ET despite higher cost. We performed an analysis to determine the cost of the difference in BC specific survival benefit when using AI compared to T in the adjuvant treatment of HRP BC in PoM W. Methods: Prices of medications were obtained through First Data Bank Blue Book. Annual incidence of BC globally was taken as reported in GLOBOCAN 2008. Incidence of non-metastatic, HRP BC in PoM W was calculated using data on incidence of metastatic BC (6%), HRP BC (80%) and W with PoM status (75%) from Cancer Statistics 2009 and Anderson WF et al, 2002 respectively. Meta-analysis of ATAC and BIG-98 trials comparing 5 years (yrs) of T and AI (T and anastrozole/letrozole), in the adjuvant setting presented by Dowsett et al, JCO, Vol 28, No 3 (January 20), 2010: 509-518 was used for calculating BC specific survival benefit of AI over T.

Results: Annually, 780,307 W globally would be eligible for 5 yrs of adjuvant ET. The cost of 5 yrs treatment for these W with T vs. AI is $5.4 billion (B) United States dollars (USD) vs. $22.5 B USD, respectively. The absolute BC specific survival benefit of treating W with AI over T for 5 yrs was 1.1%. Therefore, treating 780,307 women with AI rather than T for 5 yrs would benefit about 8583 W from BC specific mortality. The cost for saving one woman from BC related mortality, if treated with AI rather than T would be $1,992310.38 USD [(22.5 B USD — 5.4 B USD/8583]. AI use was associated with fewer endometrial cancers and thromboembolic events than T but with more arthralgias and fractures. Conclusion: AIs have shown benefit over T, but applying those results en-mass to all patients with HRP BC might be a substantial economic burden on society with relatively small benefits. Target markers for subset of patients who might preferentially benefit from AIs more than T need to be identified to best optimize the benefit from these drugs. Each class of drugs have different side effect profiles which should help individualize treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-09-03.
Abstract P1-09-06: Imaging Tests in Staging and Surveillance of Early Breast Cancer (EBC) — Changes in Routine Clinical Practice and Cost Implications
Authors: Arpino G , Cammarota S , Ianniello G , Genua G , Febbraro A , Mastrogiacomo F , Mabilia R , Pisano A , Bianco M , Barbato E , Daniele B , Savastano C , Del Prete S , Malorni L , De Placido S.
Published: April 2011

Background. New imaging tests such as computed tomography [CT], [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning and magnetic resonance imaging (MRI) are not recommended for staging or follow up of asymptomatic patients with EBC according to current guidelines. However, frequently these tests are requested even in the absence of a clinical indication. Variations in practice patterns have significant cost implications and no clear impact on cancer outcomes. Aim. In the present study we analyzed how the availability of novel and more expensive imaging technique has changed staging and follow-up modalities in EBC patients and if these changes affect costs. Methods. Two thousand and five patients with EBC diagnosed between January 2005 and December 2008 were identified using clinical computerized medical records from 639 general practitioners assisting 915,689 inhabitants of the Campania, a southern region of Italy. For each year EBC incidence, the mean number of diagnostic tests per patient (N/Pt) done during the first year after the initial diagnosis and the mean costs per each year were evaluated and compared by Anova test. Results. We identified 576, 489, 474 and 497 newly diagnosed cases of EBC in 2005, 2006, 2007 and 2008 respectively.

Table 1

Table 1 describes changes in the mean number of different imaging tests requested per patient in these years. Overall, there was a significant increase of the mean number of imaging tests done per patient from 2005 to 2008 (P<0.0001). No change of the mean number of mammograms, bone scan and chest X ray requested per patient was observed. However, importantly, the mean number of TC scan, PET scan and MRI requested per patient almost doubled from 2005 to 2008. Accordingly, the mean costs for staging and surveillance per patient also significantly increased (355 € in 2005, 378 € in 2006, 391 € in 2007 and 547 € in 2008; <0.0001).

Conclusions. TC scan, PET scan and MRI employment for patient with EBC in daily clinical practice has been steadily growing over the past four years. However, there are no data to support their role in routine breast cancer staging or surveillance in asymptomatic patients. More studies are needed to characterize which subset of patients deserve more intensive staging and follow up procedures as costs related to these imaging test prescriptions are relevant.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-09-06.
Abstract P1-10-07: Preferences for Gender of Surgeon among Women with Breast Cancer
Authors: Freed DH
Published: April 2011

Background: Hospitals have aggressively recruited and marketed women breast surgeons without evidence that women with breast cancer prefer them. Research about preferences could improve future decision making, with positive effects on patient satisfaction and health outcomes, hospital clinical and financial performance, and surgeon supply and workload distribution. The purpose of this study was to develop a grounded theory of preferences for gender of surgeon among women with breast cancer that is based upon exploratory research guided by two principal research questions:

1. What are the major categories to emerge from interviews with women with breast cancer about preferences for gender of surgeon?

2. How do women with breast cancer form preferences for gender of surgeon?

Material and Methods: A university-based survey research unit conducted semi-structured, random digit dialing telephone interviews with 12 Rockland County, NY women age 40-80 regarding factors of importance, including gender, when they actually or prospectively considered what surgeon to visit for breast cancer care. The researcher then used principles of thematic analysis to systematically categorize and make sense of interview data. Institutional review board approvals and multiple methods of verification were both provided for.

Results: Women recited both evaluative criteria used to compare surgeons and determinant attributes actually used to differentiate among choices, but gender did not emerge spontaneously in either case. Four categories did emerge: surgeon, hospital, clinical scenario, and office practice. A central category described the relationship between women's preferences and surgeons’ attributes: hierarchy of effects among women's beliefs, feelings, and behaviors. Women informed their preferences through a deliberate, well-informed process of active research, not stereotypes. Discussion: Gender may act to mediate preferences once other threshold categories are accounted for. Future research using quantitative methods is feasible. Hospitals that seek to promote breast surgery services should first, become valued information resources; and second, recruit and market surgeons according to competence and not gender as a principal criterion.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-10-07.
Abstract P1-10-11: Outcome of Patients with Early Breast Cancer Is Not Related to Their State of Social or Health Insurance
Authors: Jueckstock JK , Rack BK , Janni WJ , Brandelik A , Scholz C , Friese K.
Published: April 2011

Background: Recent studies in the US showed a relationship between the state of social or health insurance of cancer patients and their overall survival. [1-3] In Germany 91% of all women are estimated to have a compulsory health insurance whereas 9% have private health coverage. There are no patients without any health insurance in Germany.

Patients and Methods:

In a retrospective analysis of 1846 german patients with early breast cancer the correlation between state of social and health insurance and overall survival was investigated. 59.6% of the patients had a social insurance whereas 40.4% had none. 69.1% of the patients carried compulsory health insurance while 30.9% had private coverage.

Among the patients with compulsory health insurance 56.6% had had a professional education and 41.5% were employed whereas among the patients with private coverage 66.2% were professionally experienced and 43.9% were working.

Age, tumor size, lymph node metastases, grading and both hormone and

her2-status were well balanced between the two groups.

25.4% of all patients had undergone mastectomy and 72.6% had had

a breast conserving therapy. In 2.0% of the patients no surgery was

performed.

33.6% of all patients received adjuvant chemotherapy while endocrine therapy or radiotherapy was administered to 40.1% and 61.1% respectively.

Results:

Overall survival as expected was strongly correlated to established prognostic factors such as age, tumor size, lymph node status, and grading (p< 0.001) respectively.

However, overall survival of the patients did not correlate to either social (p= 0.110) or health (p= 0.659) insurance state. Neither did the professional education of the patients play a role concerning overall survival (p=

0. 217.. Conclusions:

Unlike the American results there was no correlation seen between state of social or health insurance for german early breast cancer patients. Thus, although patients with private coverage are supposed to receive more intensive medical care, outcome for these patients concerning overall survival is not better than for patients with compulsory insurance. Literature:

1. Banerjee M, George J, Yee C, Hryniuk W, Schwartz K.: Disentangling the effects of race on breast cancer treatment. Cancer. 2007 Nov 15;110(10):2169-77.

2. Griggs JJ, Culakova E, Sorbero ME, Poniewierski MS, Wolff DA, Crawford J, Dale DC, Lyman GH. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007 Jun 20;25(18):2522-7.

3. Brookfield KF, Cheung MC, Lucci J, Fleming LE, Koniaris LG. Disparities in survival among women with invasive cervical cancer : a problem of access to care. Cancer. 2008 Dec 18.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-10-11.
Abstract P1-11-06: Tumor-Associated Lymphocytes and Hormone Receptor Status Predict Pathological Response to Neoadjuvant Chemotherapy in Breast Cancer
Authors: Hee Jin L , Jin-Hee A , Jin Young S , Sei-hyun A , Gyungyub G.
Published: April 2011

Background: Neoadjuvant chemotherapy has been used for patients with locally advanced breast cancer and is increasingly given to patients with operable breast cancer which is not suitable for breast conserving surgery or proven lymph node metastases. Recently, tumor-associated lymphocytes in breast cancer have been suggested as a new independent predictor of neoadjuvant chemotherapy. To evaluate the predictive value of tumor-associated lymphocytes in the neoadjuvant chemotherapy of breast cancer patients, we performed this study.

Materials and Methods: Two hundred and sixty five patients received surgery after neoadjuvant chemotherapy between 2000 and 2009. We investigated the proportion of intratumoral and stromal tumor-associated lymphocytes in 212 patients with available pretreatment biopsy specimens and following three groups of chemotherapy regimens: anthracycline-based (50 patients, 23.6%), anthracycline/taxane-based (130 patients, 61.3%), and herceptin-based (32 patients, 15.1%) regimens. Combined tumor-associated lymphocyte infiltrate was obtained from the greater value of intratumoral or stromal lymphocytes. We evaluated the relationship between pathological complete response (pCR) and clinicopathological factors including combined tumor-associated lymphocyte infiltrate. The definition of pCR was the absence of residual invasive or noninvasive carcinoma in breast and lymph nodes.

Results: pCR was achieved in 17 (8.0%) patients. In the multivariate logistic regression analysis, the degree of combined tumor-associated lymphocyte infiltrate is correlated with the higher rate of pCR (p=0.024, odds ratio 1.24, 95% confidential interval 1.03-1.49). ER-and PR-negativity was also a significant independent factor of pCR (p=0.047, odds ratio 3.09, 95% confidential interval 1.01-9.42). However, cT stage, cN stage, age, chemotherapy regimen, tumor grade, HER2 positivity, and triple negativity were not significantly correlated with pCR. Conclusion: The percentage of tumor-associated lymphocytes and negative hormone receptor expression are significantly linked to pCR.

Tumor-associated lymphocytes could be considered as a new important pathologic factor to predict the response of neoadjuvant chemotherapy in heterogeneous breast cancer other than conventional biomakers.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-06.
Abstract P1-11-11: Correlation between ER/PgR/Her-2/Ki67 Expression and Response to Neoadjuvant Endocrine Therapy for HR Positive Post-Menopausal Breast Cancer
Authors: Ouyang T , Ying M , Li L , Wang T , Xie Y , Lu A , Lin B.
Published: April 2011

Background: Endocrine therapy was standard adjuvant treatment for hormone receptor positive breast cancer. However, there were factors other than receptor status could influence endocrine responsiveness. Neoadjuvant therapy was an excellent platform for predictive factors research, but the standard for evaluating the efficacy of neoadjuvant endocrine therapy was controversy. The aim of this study was to investigate the correlation among the results of different response evaluation system, and the relationships between ER/PgR/Her-2/Ki67 expression and the responses to neoadjuvant endocrine therapy for postmenopausal breast cancer.

Methods: Data of consecutive 133 core needle biopsy (CNB) confirmed hormone receptor strongly positive (more than 50% tumor cell stained ER or PgR) postmenopausal breast cancer treated with neoadjuvant endocrine therapy were analysis retrospectively. All pts. were planned to receive endocrine therapy alone as their adjuvant treatment and prescribed Anastrozole 1 mg per day for 16 weeks before surgery. Clinical response were evaluated by using documented ultrasound records,pathological response was evaluated by one senior pathologist with Miller & Payne classification. Cell cycle complete response was defined as post-treatment Ki67 ≥1%. The new slides of pre-treatment and surgical specimens were made for ER/PgR (ER\PR DakoCytomation)/Her-2 (Her-2 Dako HercepTest TM)/Ki67 (Ki67 Ventana) immunohistochemical staining through Benchmark XT Staining Instrument (Ventana Medical Systems. Inc. Arizona. USA) and classified by using image analysis system Ariol (Applied Imaging Inc., San-Jose, California, USA).

Results: Clinical response were CR:0.8% PR:33.1% SD:66.1%, pathological response were G5:3% G4+G3:47.4% G2+G1:49.6%, Ki67 change were <1%: 22.8% decrease but >1%:45.1% no decrease: 32.1%. The correlation and consistency among the response evaluated differently were poor [table 1]. The per-treatment ER/PR/Her-2/Ki67 showed low degree of correlation with responses [table 2]. Pre-treatment ER≥90% and PR≥90% and Her-2 coudln't predict better response.

The correlation and consistency among response evaluated in different system

Conclusion: The correlation and consistency among the results of response to neoadjuvant endocrine therapy evaluated by different system were poor. ER/PgR/Her-2/Ki67 showed low degree of correlation to responses. It's difficult to predict response to Arimidex neoadjuvant endocrine therapy by using ER/PgR/Her-2/Ki67 expression.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-11.
Abstract P1-11-16: Her2/neu Overexpressing Breast Cancer Patients Retain an Immunological Proficiency Compromised in Her2/neu-Negative Cases
Authors: Simona SSS , Muraro EME , Miolo GGM , Martorelli DMD , Turchet ETE , Comaro ECE , Talamini RTR , Veronesi AVA , Crivellari DCD , Dolcetti RDR.
Published: April 2011

Although breast cancers overexpressing HER2/neu are associated with a worse prognosis, a high rate of complete responses is usually induced in these patients by current therapeutic strategies, such as Trastuzumab, that also directly mediates antibody-dependent cellular cytotoxicity and possesses immunomodulating properties. Moreover, other chemotherapeutics used in this setting, i.e. doxorubicin and Taxol, were shown to enhance antigen-specific immune responses. On these grounds, a thorough evaluation of the immunologic profile of breast cancer patients may be helpful to predict clinical responses to such therapies. We therefore analyzed at diagnosis different immunological parameters of patients with locally advanced HER2+ (n=18) and HER2- (n=30) breast cancer eligible for neoadjuvant chemotherapy, respectively treated with weekly Paclitaxel (80 mg/mq/ev) and Trastuzumab (4mg/kg/ev day 1 followed by 2 mg/kg/ev weekly), or Epirubicin (90 mg/mq/ev) and Docetaxel (75mg/mq/ev) every 3 weeks. Immunophenotyping of circulating immune cells disclosed several differences in HER2- cases as compared with HER2+ patients and healthy controls (n=20). In particular, HER2- patients showed a higher percentage of NK and B cells (10.2 and 10.0%, respectively) and a lower CD4/CD8 T cell ratio (1.8; with a prevalence of naïve and central memory cells in the CD8+ population) if compared to HER2+ patients (NK 5.8%, B cells 8.2%, and CD4/CD8=2.3) and healthy controls (NK 5.5%, B cells 7.7%, and CD4/CD8=2.2). In addition, HER2- cases had higher numbers of circulating CD4+ regulatory T cells (1.6% FoxP3+CD25+CD127- of CD4+ T cells) with respect to donors (0.9%). Moreover, IFN-gamma ELISPOT assay demonstrated spontaneous T cell responses to a broad spectrum of HLA-A*0201-restricted peptides derived from breast cancer-associated antigens (HER2/neu, MUC-1, mammaglobin-A, Taxol resistance-associated gene-3, survivin, and Bcl-xL) in both groups of tumour patients, although the extent of these responses was usually higher in HER2+ cases. Finally, a multiparametric evaluation of the serum levels of 9 different cytokines revealed a comparable profile in HER2+ cases and in controls, whereas HER2- patients showed significantly lower cytokine amounts compared to healthy donors (IL-2, IL-6, and IL-8) and to HER2+ breast cancers (IL-6, IL-8, and IL-10). Preliminary data revealed a pathological complete response (pCR) in 44.4% of HER2+ patients (8/18), compared to 16.7% of the HER2- arm (5/30). These results are consistent with a retained immunologic proficiency of HER2+ patients, showing an innate tumor-specific immune response. Such features may at least partly account for the clinical benefit of drugs acting through, but also promoting, immunemediated effects.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-16.
Abstract P1-11-20: Open-Label Phase II Study of Neoadjuvant Bevacizumab Combined with FEC→Paclitaxel in Patients with Inflammatory or Locally Advanced Breast Cancer
Authors: Venturini M , Del Mastro L , Aitini E , Saracchini S , Garrone O , Durando A , De Placido S , Boni C , Levaggi A , Scalamogna R , Galli A , Clavarezza M.
Published: April 2011

Background: There is strong evidence that VEGF plays an important role in the pathogenesis and progression of human breast cancer. Bevacizumab, a monoclonal antibody, specifically inhibits VEGF. The combination of first-line bevacizumab with chemotherapy significantly improved the activity in comparison to chemotherapy alone in three randomized phase III trials in metastatic breast cancer patients (pts). In early breast cancer, the FEC→Paclitaxel regimen is a highly active standard therapy. Therefore we initiated a trial to evaluate the combination of bevacizumab with this efficacious chemotherapy regimen for the treatment of stage III or inflammatory early breast cancer (LABC).

Patients and Methods: The study is designed to evaluate a sequential regimen of FEC90 followed by the combination of paclitaxel and bevacizumab as neoadjuvant therapy in patients with HER2-negative locally advanced (stage III or inflammatory) breast cancer. Patients are treated with neoadjuvant FEC 600/90/600 mg/m2 q21d x 4, followed by paclitaxel 80 mg/m2 weekly x 12 combined with bevacizumab 10 mg/kg q2w x 6. Patients undergo surgery 4 weeks after completing chemotherapy. Pathologic complete response (pCR), the primary endpoint, is defined as no evidence of invasive tumor in the final surgical sample both in the breast and axilla. Secondary endpoints include objective clinical response rate (RR), disease-free interval, overall survival, rate of breast-conserving surgery, and the safety of the regimen.

Results: Between Feb 2008 and Dec 2009, 54 pts (mean age of 51±7.5 years) were enrolled into the study. To date, 32 pts have completed neoadjuvant treatment and surgery and are evaluable for response. Baseline characteristics in these 32 patients were as follows: cT3/cT4b: 20 (63%) and/or cN2/cN3: 14 (43%); estrogen receptor (ER) positive: 24 (75%) and 8 (25%) triple-negative (TN), defined as ER negative, progesterone receptor-(PgR-) negative, and HER2 negative. Histological type was ductal carcinoma in 24 patients (75%), lobular carcinoma in 4 (13%), inflammatory breast cancer in 1 (3%), and other in 3 (9%). Mastectomy was performed in 22 patients (69%) and breast-conserving surgery in 10 patients (31%). After neoadjuvant treatment, 8/32 patients (25%) achieved a pCR.

Conclusions: This open-label, multicenter, phase II study demonstrated that the FEC→Paclitaxel plus bevacizumab combination is a highly active neoadjuvant treatment for HER2-negative locally advanced breast cancer. A 25% of pCR in this group of pts with high tumor burden, i.e. the LABC, is oneof the most promising chemotherapeutic regimen if confirmed in the final analyis. Results for all 54 pts enrolled will be presented at the meeting.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-20.
Abstract P1-12-03: The STAGE Study: A Phase III Comparison of Anastrozole Plus Goserelin with Tamoxifen Plus Goserelin as Pre-Operative Treatments in Premenopausal Breast Cancer Patients
Authors: Sagara Y , Masuda N , Kinoshita T , Iwata H , Nakamura S , Yanagita Y , Nishimura R , Iwase H , Kamigaki S , Takei H , Noguchi S.
Published: April 2011

Background: Although superior antitumor activity of anastrozole over tamoxifen has been well established in postmenopausal breast cancer patients, it still remains to be examined whether or not anastrozole is superior to tamoxifen in premenopausal breast cancer patients whose ovarian function is suppressed by goserelin to postmenopausal levels. The aim of this study was to compare anastrozole plus goserelin versus tamoxifen plus goserelin as pre-operative treatment for premenopausal Japanese women with breast cancer.

Methods: Phase III, randomized, double-blind, parallel-group, multi-center study (D539BC00001). Premenopausal patients (pts) with ER-positive and HER2-negative breast cancer and with operable and measurable lesions (T [2-5 cm], N0, M0) were randomized 1:1 to receive a goserelin 3.6 mg depot injection once monthly plus either anastrozole 1 mg (A+G) or tamoxifen 20 mg (T+G) p.o. once daily. Treatment continued for 24 weeks prior to surgery or until any other criterion for discontinuation was met. Concomitant chemotherapy was not permitted during the pre-operative period. The primary objective was to assess the best overall tumor response (either a complete response [CR] or a partial response [PR]), according to modified RECIST criteria. Tumor size was measured by caliper and ultrasound every 4 weeks and by magnetic resonance imaging/computed tomography (MRI/CT) every 12 weeks. Tolerability (adverse events [AEs], laboratory tests, vital signs, WHO performance status) was assessed as a secondary objective. AEs were evaluated according to CTCAE v3.0.

Results: In total, 197 pts were randomized (A+G: 98, T+G: 99) and 185 pts completed the 24-week pre-operative treatment period and went on to receive breast surgery. The remaining 12 pts discontinued study treatment due to disease progression (A+G: 1; T+G: 5), voluntary discontinuation (A+G: 2; T+G: 3) and AE (T+G: 1). Pt demographics were generally well balanced. Median duration of exposure was similar for A+G (171 days) and T+G (170 days); treatment compliance was 99% for both. A+G led to a statistically significantly higher overall response rate compared with T+G, by caliper as well as by ultrasound and MRI/CT.

The safety profiles were consistent with the known safety profile of anastrozole, tamoxifen and goserelin. The incidence of AEs was similar

for A+G (88.8%) vs T+G (85.7%); most AEs were mild or moderate (CTC grade 1 or 2). The most common AEs were hot flash (A+G: 52.0%; T+G: 53.1%) and arthralgia (A+G: 35.7%; T+G: 20.4%). Conclusion: This study has demonstrated that the A+G combination has a superior benefit-risk profile compared with T+G as pre-operative treatment in Japanese premenopausal women with ER-positive breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-03.
Abstract P1-12-05: Factors Affecting Local Recurrence after Breast Conserving Surgery Following Neoadjuvant Endocrine Therapy with Letrozole
Authors: Dixon JMJ , Renshaw L , Keys J , Leeper AD , Williams L , Evans DB.
Published: April 2011

Background

Few data exist on local recurrence rates after breast conserving surgery in post menopausal patients following neoadjuvant endocrine therapy with letrozole. The aim was to investigate the outcome of a large series of patients treated in the Edinburgh Breast Unit. Patients

208 patients underwent breast conserving surgery after at least a 3 month course of neoadjuvant letrozole. The median age was 77 years (range 51 to 93). Of these patients 73% (151/208) received postoperative radiotherapy.

Median follow up was 2.95 years (range 0.28 to 8.43)

Results

At two years 97% were local recurrence free and by five years 95% were recurrence free. By the Log Rank (Mantel-Cox) non-parametric method of analysis, there was a significant difference between patients treated by postoperative whole breast radiotherapy (RT) compared with no radiotherapy (p=0.02). There were very small numbers of local recurrences (five in no RT group, two in RT group by the end of five years). At two years 93% of patients with no RT were recurrence-free, compared with 98% of those with RT, at five years this is 86% and 98% respectively There was a borderline significant difference between HER2 positive and negative breast cancers, (p=0.055). At two years 97% of HER2 negative patients were recurrence-free, compared with 91% of HER2 positive patients. At five years, it was 96% and 85% respectively. Death from other causes was very common in this elderly age group and the median survival time was 7.2 years (95% CI 5.8 to 8.5). 90% of patients survived to the end of two years (95% CI: 86% to 94%), while only 68% survived to the end of years (60% to 76%).

By the Log Rank test, there was a significant difference between patients treated by radiotherapy and those who did not receive radiotherapy (p=0.004). The median survival with no RT was 4.7 years (95% CI: 3.7 to 5.8) and for patients following RT was 8.1 years (95% CI: 6.2 to 10.0). The reason for this was selection of fitter patients for radiotherapy and avoiding radiotherapy in frail patients.

Conclusions

Local recurrence after breast conserving therapy following neoadjuvant endocrine therapy with letrozole is uncommon in this group of patients. Following radiotherapy local recurrence is only 2% at 5 years. Rates of recurrence are over 10% at 5 years without radiotherapy. HER2 positive patients have a higher local recurrence rate than HER2 negative patients.

Breast Conserving Surgery followed by whole breast radiotherapy produces excellent rates of local control in postmenopausal women following neoadjuvant endocrine therapy with letrozole.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-05.
Abstract P1-12-07: Neo-Adjuvant Exemestane in Post Menopausal Estrogen and/or Progesterone Receptor Positive Breast Cancer: A Randomized Phase II Trial To Investigate Optimal Duration (4 Month Versus 6 Month) of Preoperative Endocrine Therapy (PTEX46 Trial)
Authors: Hojo T , Kinoshita T , Wada N , Imoto S , Tamura N , Nagao T , Ando M , Katsumata N , Fujiwara Y.
Published: April 2011

Background: Since the 1990s, primary endocrine therapy has been considered the gold standard in the adjuvant and metastatic treatment settings for estrogen and/or progesterone receptor (ER and/or PgR) positive breast cancer. This therapy has also been shown to be effective as neo-adjuvant endocrine therapy in these indications. In recent years, the focus of clinical interest has shifted to the third-generation aromatase inhibitors from tamoxifen. The optimal treatment duration time and causal relationship between neo-adjuvant endocrine therapy and survival, however, are not clear. We therefore conducted the present study to investigate the potential benefits of neo-adjuvant exemestane (E) therapy with the goal of identifying the optimal treatment duration (4 months versus 6 months).

Methods: Conducted at three hospitals in Japan, this study was a multicenter, randomized phase II trial of pre-operative E treatment in postmenopausal women with untreated primary breast cancer. Fifty postmenopausal women with ER positive and/or PgR positive invasive breast cancer were randomly assigned to E (25 mg/day) for 4 months (4 mo) or E (25 mg/day) for 6 months (6 mo). All patient data were collected by UMIN and were analyzed by the National Cancer Center in Japan. Tumor regression (by clinical examination, ultrasound, and MRI), pathological response, shift towards breast-conserving surgery, and safety assessments were the main outcome measures.

Results: Of the 50 patients that enrolled, 28 patients had undergone surgery. The mean ages in the 4 mo and 6 mo treatment groups were 66.7 years and 66.8 years, respectively. No significant differences in the patient characteristics were found in the two groups. The response rates (partial or complete responses) by clinical examination in the 4 mo and 6 mo groups were 37.5% and 50%, respectively. Pathological responses (minimal response or better) were found in 13.3% and 41.7% of patients and a partial mastectomy was performed in 50.0% and 58.3% of patients after 4 mo and 6 mo, respectively.

Conclusion: To date, the results of this study demonstrate that treatment with E for 6 mo was more efficacious than treatment with E for 4 mo. Further work is in progress to obtain data from additional patients and to identify the optimal duration of neo-adjuvant E.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-07.
Abstract P1-13-01: Comparing the Effects of Denosumab and Zoledronic Acid on Pain Interference with Daily Functioning in a Randomized Phase 3 Trial of Patients with Breast Cancer and Bone Metastases
Authors: Cleeland CS , Patrick DL , Fallowfield L , Clemons M , Lipton A , Masuda N , Qian Y , Braun A , Chung K.
Published: April 2011

In a recently completed trial of breast cancer patients with bone metastases, denosumab, a fully human monoclonal anti-RANKL antibody, was superior to zoledronic acid (ZA) in delaying/preventing skeletal-related events. Between-treatment differences in patient-reported pain interference with daily functioning were assessed.

Eligible breast cancer patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg (double-bind, double-dummy design). Patients completed the Brief Pain Inventory (BPI) to assess pain severity and interference with daily functioning (range 0 [does not interfere]-10 [interferes completely]) at baseline (BL), day 8, and before each monthly visit through end of study. The BPI interference scale generated a total interference score as well as an activity subscale (interference with walking, general activity, and work) and an affective subscale (interference with relations with others, enjoyment of life, and mood). Analyses were conducted on all randomized patients with ≥1 PRO assessment and were performed through week 73, when 30% of patients had dropped out due to death, disease progression, or consent withdrawal. Subgroups included patients with no/mild and moderate/severe worst pain at BL. Analyses included time to improvement (≥2-point decrease) or worsening (≥2-point increase) in pain interference, mean change from baseline, and proportion of patients with improving or worsening pain interference scores. Time to improvement in pain interference with activity (PIWA) tended to occur more quickly with denosumab compared with ZA (N=1124; median: 70 days denosumab v 86 days ZA; P=0.09), and time to worsening PIWA tended to be longer with denosumab compared with ZA (N=1676; median: 394 days denosumab v 310 days ZA; P=0.13). In patients with no/mild pain at BL, denosumab also demonstrated a trend for shorter time to improvement in PIWA (N=388; 93 days denosumab v 120 days ZA; P=0.06) and longer time to worsening PIWA (N=755; 369 days denosumab v 232 days ZA; P=0.12). Overall, a greater proportion of patients on denosumab had improvement in PIWA on study than ZA (Figure). Findings were similar with the total interference score and affective subscale.

Figure Proportion of Patients With Improvement in Pain Interference With Activity (≥2-point decrease from BL)*

Daily functioning (total interference and interference with activity and affect) tended to be less disrupted by pain in patients on denosumab compared with ZA. Decreased pain interference showed a trend to occur more quickly with denosumab. Overall, a greater proportion of denosumab patients reported decreased pain interference than ZA patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-01.
Abstract P1-13-04: Immunohistochemical Evaluation of RANK/RANKL/OPG Axis and CXCR4 in Primary Breast Cancer and Their Role in Bone Metastasization
Authors: Ibrahim T , Sacanna E , Gaudio M , Mercatali L , Ricci R , Scarpi E , Serra P , Fabbri F , Serra L , Amadori D.
Published: April 2011

Background: The RANK/RANKL/OPG axis plays an important role in the bone metastasization process. CXCL12 is overexpressed in bone and, like its receptor, CXCR4, is a determinant of organ tropism. The objective of the present study was to evaluate whether the expression of these markers in primary breast cancer can predict the onset of bone metastases. Methods: Marker expression was evaluated by immunohistochemical staining in paraffin-embedded sections of primary breast cancers from 40 individuals: 10 patients (median age 64 years, range 48-78) showed no evidence of disease (NED — control group) at a median of 9.8 (range 6.9-11.5) years, while 30 (median age 67 years, range 42-87) had relapsed. In the latter group, 10 (median age 66 years, range 42-87) had visceral metastases (VM — control group) and 20 (median age 69 years, range 42-87) had bone metastases (BM — case group), both confirmed radiologically. The 3 patient subgroups (NED, visceral lesions, bone lesions) were matched for age classes (≥60 years, > 60 years). The study design was reviewed and approved by the local ethics committee.

Results: In the overall series, 17.5% of tumors were positive for RANK, 22.5% for OPG and 25% for CXCR4. None of the patients expressed RANKL. RANK and OPG resulted equally expressed in 20% of NED patients, while CXCR4 was expressed in only 10% of this group. OPG was expressed in 20% of VM patients, whereas RANK or CXCR4 were not detected. RANK and OPG positivity was present in 25% of BM patients, while CXCR4 was expressed in 45% of cases. CXCR4 was the only marker with a significantly higher frequency of expression in bone metastases than in visceral lesions (p=0.013). Taking into consideration all the patients without bone involvement (NED plus VM patients), it was observed that CXCR4 expression, alone and in combination with RANK, significantly discriminated between BM patients and the control group (p=0.008 and P<0.001, respectively). ER-positivity and HER2-negative status were observed in 80% and 95% of BM patients, respectively, but neither discriminated between cases and controls. Conclusions: In our study, ER-positivity and HER2- negativity identified a high percentage of bone relapse patients, but also highlighted patients who did not have bone involvement. RANK and CXCR4 expression, on the other hand, would appear to be a more accurate predictor of bone relapse. Such evidence could help to identify patients with a high probability of developing bone metastases, which can be treated with bisphosphonates or other bone-targeted therapies, such as denosumab, in an attempt to prevent distant metastases. Our results are currently being validated in a larger series of breast cancer patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-04.
Abstract P1-13-06: Health Resource Utilization Associated with Skeletal-Related Events in Patients with Bone Metastases: Interim Analysis Results from the US Breast Cancer Cohort of a Multinational Observational Study
Authors: Mahmood A , Robles R , Ghazal H , Atchison C , Wei R , Chung K , Pinzone J.
Published: April 2011

Background: Bone metastases are common in women with advanced breast cancer and are frequently associated with skeletal-related events (SREs). The burden of individual SRE types on health resource utilization (HRU) indicators in breast cancer has been only minimally described. Methods: The aim of this ongoing observational, prospective, multinational study is to assess, by tumor type, the amount of HRU associated with different SRE types including pathologic fracture, surgery or radiation to bone, and spinal cord compression. Patients with breast, prostate, or lung cancer and bone metastases or multiple myeloma were enrolled after experiencing a SRE. Inpatient hospitalizations, length of stay, outpatient visits, emergency room visits, nursing home/long-term care facility stays, home health visits, procedures, and medications were collected for the period 90 days prior to enrollment and prospectively to a maximum of 18 months. Each patient could contribute multiple SREs. The investigator determined which HRU were attributed to each SRE. This abstract describes interim analysis data from the US breast cancer cohort; final analysis data will be available 9/2010.

Results: As of 12/1/2009, 67 patients contributed 119 SREs for the HRU analyses across 25 US sites. Patient mean [SD] age was 61 [12] years, all patients were female, and 27% discontinued the study (most due to death). Mean duration of follow-up was 9.9 months. HRU for each of the SRE types are shown in the table.

Table. Mean and median number of HRU per SRE during the study period by SRE type in patients with breast cancer

Conclusion: In this interim analysis of advanced breast cancer patients in the US, SREs are associated with considerable HRU, with the nature and extent of HRU varying depending on the SRE type.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-06.