bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Older Age on Presentation and Management of Breast Cancer in the Multi-Ethnic Population of Singapore.
Authors: Verkooijen H. , Verkooijen H. , Saxena N. , Hussain Z. , Lim S. , Hartman M. , Chia K. , Lee S.
Published: December 2010

Background: Studies in Caucasian populations have shown that older breast cancer patients are less likely to be treated according to standard guidelines and that this under-treatment is strongly associated with impaired survival. In Asia, where population sizes and life expectancy rates are rising, the number of older women developing breast cancer is growing rapidly. This study aims to evaluate characteristics and treatment patterns of older breast cancer patients in the multi-ethnic population of Singapore, where breast cancer rates have tripled over the past three decades.Methods: This study includes all 2547 women, diagnosed with breast cancer between 1995 and 2006 at the National University Hospital in Singapore. Patients were classified into younger (< 65 years, n=2220) and older (>= 65 years, n=327). Differences in patient and tumor characteristics and treatment between older and younger age groups were explored using multivariate logistic regression models.Results: Even though older Singapore breast cancer patients had more favorable tumor characteristics than younger ones (better tumor differentiation, more often expressing estrogen and progesterone receptors), they presented significantly more often with stage III (adjusted Odds Ratio [ORadj] 1.57, 95%CI 1.0-2.4) and metastatic disease (ORadj 4.3, 95%CI 2.9-6.5). Elderly women were at increased risk not to receive breast surgery (ORadj 1.61, 95%CI 1.0-2.6) and axillary clearance (ORadj 1.74, 95%CI 1.2-2.6). In case of stage I disease, older women were significantly less likely than younger women to be treated with breast conserving surgery (ORadj 0.31, 95%CI 0.2-0.5).Conclusion: Similar to their Caucasian counterparts, older Asian breast cancer patients in Singapore are diagnosed at a later stage and receive less often standard treatment than younger women. Further studies are being undertaken to estimate the impact of these discrepancies on outcome.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3078.
Distant Metastasis Free Survival (DMFS) in Breast Cancer Patients with Micrometastases (pN1mi) in the Sentinel Lymph Node (SLN): Results in 582 Positive-SLN Patients in a Single Institution.
Authors: Alran S. , Toupet A. , De Rycke Y. , Pierga J. , Fourchotte V. , Falcou M. , Sigal-Zafrani B. , Salmon R.
Published: December 2010

Background:The risk of developing distant metastases (DM) in pN1mi and isolated tumor cells (pN0i+) patients remains under question. Does occult axillary node metastases is an additional factor for using an adjuvant systemic therapy (AST) in early breast cancer ?Patients and Methods:Among 2695 patients operated on from 2000 to 2006 for SLN, 582 patients had a positive SNB: 307 were pN1, 154 pN1mi and 121 pN0i+ (6th AJCC-classification). All patients underwent an immediate or delayed Axillary Lymph Node Dissection (ALND). We report the results for DMFS [median follow-up of 56 months (2-105)].We used Kaplan-Meier method and Cox regression for multivariate analysis.Results:ALND were positive in pN1, pN1mi and pN0i+ patients respectively in 127 (41,3%), 20 (13%) and 14 (11.6%) of these patients. On univariate and multivariate analysis, positive ALND, mitotic index, pathologic tumor size were significantly related to the DMFS; on multivariate analysis, the type of axillary lymph node metastases was an additional significative factor. There was not relationship between pN0i+ and the development of DM. Surprisingly, patients with pN1mi had a 2.8 higher risk for developing DM than pN1 patients. pN1 patients receive more AST than pN1mi (75% and 22%), however AST was not prognostic (p=0.49).Conclusion:In our series, patients with pN1mi were associated with a worse prognosis related to DMFS compared to pN1. Use of AST and/or biological primary tumor characteristics could explain this paradoxical result. Longer follow-up and larger series are needed to determine the prognostic significance of axillary occult metastases.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 308.
Promising Practices in Mammography Recruitment, Retention and Rescreening for Breast Cancer Early Detection among Community-Based Programs Supported by the Avon Foundation Breast Care Fund.
Authors: Hurlbert M. , McDonnell C. , Gates-Ferris K. , Opdyke K. , Pagaduan M. , Chi B.
Published: December 2010

Background/Significance: National guidelines recommend women age 40 and older have mammograms every 1-2 years. Since 2000, the Avon Foundation Breast Care Fund (AFBCF), a project of Cicatelli Associates Inc., has supported nonprofit community-based organizations (CBOs) to provide breast health education and outreach to link medically underserved women with free/low-cost breast cancer screening services. These organizations have developed effective strategies for recruiting, retaining and rescreening clients. This evaluation study aims to identify promising practices for effective mammography recruitment, retention and rescreening among un/underinsured, low-income, and racial and/or ethnic minority women.Methods: Twenty of 144 AFBCF-funded CBOs were selected to participate in a retrospective study to determine clients' rescreening rates.CBOs provided de-identified data on mammography screening by age and visit date to determine their rescreening rate, defined as the proportion of female outreach clients age 40+ years receiving a mammogram and subsequent mammogram through that agency within the following 6-18 and/or 18-30 months. CBOs also completed a qualitative survey about program strategies and systems. Qualitative data were linked with rescreening rates to identify promising practices. Survey results were also used to develop a discrete questionnaire administered to 144 AFBCF-funded CBOs to identify which agencies currently employ identified promising practices.Results: Data analysis will be completed in September 2009.Preliminary results indicate that rescreening rates vary widely across agencies, from 15% to over 90%. In addition, findings indicate that some CBOs lack mechanisms to routinely monitor client rescreening. Utilizing unique client identifiers in conjunction with the use of electronic data tracking systems would facilitate tracking clients over time and improve targeted outreach efforts to increase rescreening rates.Discussion: Combined qualitative and quantitative analyses of differences in practices directed at encouraging mammography rescreening among medically underserved women will enable a description of promising practices for increasing rescreening rates in this population. Analysis will include an explanation of mammography rescreening rates among medically underserved women. Agencies with high rescreening rates will be identified and discussion regarding organizational characteristics and practices will be presented. Additionally, unique and innovative strategies for reaching specific populations will be examined.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3080.
Post-Mastectomy Breast Reconstruction among the Largely Hispanic Underinsured of Southern California: An Analysis of Factors Leading to Lower Referral and Reconstruction Rates over Two Decades.
Authors: Mussman J. , Modad G. , Kalina S.
Published: December 2010

Background: This study investigates improvements in the rate of reconstruction over the last decade for the, predominantly Hispanic, county hospital population of Riverside County, California. This is accomplished be comparison to a similar study within the same institution by Kalina et al for the preceding decade. In addition, comparisons to national trends are also made as a global measure of the success of the reconstructive process in the study population. While previous national studies have focused solely on reconstructive rates, the present study also examines post-mastectomy referral rates. Additional investigation was carried out into the factors affecting both referral and reconstructive rates within this population.Methods: A retrospective review of all female patients' charts who underwent mastectomy from Aug 1998- June 2007 was performed. Factors investigated in relation to referral and reconstruction rates were stage of the cancer, smoking status, race, surgeon performing mastectomy, and age. Ten studies were selected for comparison that represented reconstruction rates from various national database and single institution studies from 1984-2003. Logistic regression was used to analyze the data.Results: n=163. Mean Age 52. Hispanics comprised 42% followed by whites at 26%. Eighty seven (53%) patients were referred to plastics for reconstruction and 24 (15%) underwent reconstruction. There was a 273% and 333% increase compared to the previous decade in referral and reconstruction rates respectively within the study population. Rate of reconstruction (15%) within the study population was 58% lower than what was projected by national trends (36%). The surgeon performing the mastectomy was the most significant factor affecting referral (odds ratio 3.35). Younger age (<45) also led to significantly more referrals to plastic surgery (odds ratio 2.68). Prognosis, radiation therapy, and race had no significant impact on referral or reconstruction rates.Conclusions: Significant gains have been made in the rates of postmastectomy referral and reconstruction over the last decade within the county hospital population of Riverside County, California. However, comparisons with national trends indicate that the rate of reconstruction has fallen to less than half of what has been reported throughout the nation. A low referral rate to plastic surgery has been the reason for the low the reconstruction rate. The main contributing factor to whether a patient was referred was surgeon bias among the primary surgeons performing the mastectomy. The authors urge protocol driven referral patterns surrounding breast cancer diagnosis be adopted in every hospital to circumvent any bias that may exist.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3081.
Wait Times and Diagnostic Pathways among Women with Invasive Breast Cancer in a Population-Based Publicly Funded Cancer Centre, British Columbia, Canada.
Authors: Martin L. , Banno B. , Joffres M. , Wong F. , Sherriff C.
Published: December 2010

Rationale and background: The Fraser Valley Cancer Center serves a large geographic population of urban and rural areas. Selected data on wait times and diagnostic pathways are available for mammography screening programs in British Columbia (BC), but not for patients presenting with clinical abnormalities such as a palpable breast lump. Diagnostic pathways in BC are managed by primary care physicians and community surgeons. Anecdotal evidence from oncology services suggests large variation in wait times and pathways.Objective: To examine time intervals and pathways between the detection of a breast abnormality and formal assessment by medical or radiation oncology for adjuvant treatment.Methods: Retrospective chart review of all patients with a new diagnosis of breast cancer first seen at the Fraser Valley Cancer Center in 2002, linked with demographic and other registry data. Data collected included type, location, date of investigations, surgical procedures, diagnosis, treatment and stage. Exclusion criteria were patients initially diagnosed with metastatic breast cancer, patients with recurrent breast cancer, male breast cancer patients, patients diagnosed or previously treated outside BC. Microsoft Access and SAS 9.2 were used to enter and analyse data.Results: From a total of 513 women diagnosed in 2002 with invasive breast cancer, 422 women (82%), without metastases (age 30 to 97 yrs, median 59 yrs), presented with abnormal screen (45%), breast lump (47%) or other findings. These women had up to 7 different radiological breast investigations and up to 5 surgical interventions. About 5% had 5 or more breast investigations. Median time (days) from presentation to first surgery was 41 days and varied by location of first investigation. Time to surgery was highest among women who presented with abnormal screening mammogram (median 49 days). Median time from first surgery consultation to first surgery was lowest for women presenting with breast lumps (15 days).Conclusions: These data indicate wait times beyond national and international targets and identified wide variability and some inefficient, redundant or unnecessary steps. Recognition and analysis of abnormal pathways will guide changes in breast health service delivery.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3083.
Phase II Study of Sorafenib with Anastrozole To Overcome Resistance to Aromatase Inhibitors (AIs) in Patients with Hormone Receptor Positive (ER/PR+) AI Resistant Metastatic Breast Cancer (MBC).
Authors: Isaacs C. , Wilkinson M. , Liu M. , Ottaviano Y. , Chung G. , Warren R. , Jennifer E. , Cohen P. , Smith K. , Novielli A. , Castle J. , Slack R.
Published: December 2010

Background: Studies are focusing on agents which may overcome endocrine therapy resistance in patients with hormone receptor positive (ER/PR+) MBC. Activation of the Ras-Raf-MAPK pathway has been proposed as a mechanism of resistance to AIs. Thus, we are evaluating the use of sorafenib (SOR), a multi (Raf)-kinase inhibitor targeting both tumor cells and the tumor vasculature in patients with AI-resistant MBC.Methods: We are conducting a phase I/II study of SOR in combination with anastrozole 1 mg po daily (ANT) in MBC patients utilizing an optimal 2-stage design. Eligible patients include post-menopausal women with ER/PR+ MBC with disease recurrence or progression on an AI. Participants may not have received > 2 prior chemotherapies for MBC. Primary objectives are to determine the recommended dose and clinical benefit rate (CBR) (CR, PR and SD ≥ 24 weeks) of SOR with ANT. Secondary objectives are to determine toxicity, enumerate circulating endothelial cells (CECs) as an angiogenesis biomarker, and analyze the effect of treatment on CYP3A4-metabolized steroids.Results: 0/3 patients in cohort 1 (200mg BID) and 0/3 in cohort 2 (400mg BID) had dose-limiting toxicities in cycle 1. Thus, our recommended Phase II dose of SOR was 400 mg BID. Interim analysis of the first 12 patients showed >30% CBR, allowing for continued accrual to planned 35 patients. All patients had ECOG PS of 0-2. The median age was 55 years. Among 35 enrolled patients, 5 had stable disease for > 24 weeks, 2 had durable PR > 6 months, and 19 had progressive disease before 6 months. 8 patients were not response-evaluable. 1 patient on active therapy is too early to evaluate response. Clinical benefit rate is 20%. Adverse events (AEs) were generally Grade 1/2. The most common AEs (all; Grade 3/4) were fatigue (66%; 14%), diarrhea (54%; 6%), nausea/vomiting (60%; 9%), and skin rash of any kind (66%; 43%) including hand-foot syndrome (57%; 34%). G3/4 hypertension occurred in 11%. Preliminary analysis suggests that decrease in CECs from baseline to 1 week after treatment predicts for a response. Correlative science analyses are ongoing.Conclusions: The combination of SOR and ANT in patients with ER/PR+ AI-resistant MBC demonstrated an encouraging 20% CBR and is worthy of further study. A decrease in CECs appears to predict response. Toxicity with 400 mg po bid SOR occurred frequently but was manageable with dose reductions. Given the negligible activity of single-agent SOR in MBC, we believe that the benefit may be attributable to the restoration of sensitivity to AIs through inhibition of the Ras-Raf-MAPK pathway. Supported Patient for Progress Award 3 P30CA051008-15S3 and Sorafenib provided by CTEP-NCI.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3090.
Ridaforolimus (AP23573; MK-8669) in Combination with Trastuzumab for Patients with HER2-Positive Trastuzumab-Refractory Metastatic Breast Cancer: A Multicenter Phase 2 Clinical Trial.
Authors: Yardley D. , Seiler M. , Ray-Coquard I. , Melichar B. , Hart L. , Dieras V. , Barve M. , Melnyk A. , Dorer D. , Turner C. , Dodion P.
Published: December 2010

Background: Trastuzumab (T) resistance may be due to aberrant signaling through the PI3K/Akt pathway. Pre-clinical and retrospective clinical data suggest that mTOR inhibition can overcome this mechanism of trastuzumab resistance. Ridaforolimus (R), an mTOR inhibitor, in combination with HER2 inhibition offers the potential for vertical pathway synergy.Methods: A single-arm, two-stage phase 2 trial was performed to evaluate R combined with T. Eligibility criteria included: female patients with HER2+ (IHC 3+ or FISH+) metastatic breast cancer (MBC), age ≥18 years, ECOG performance status ≤ 1, RECIST criteria measurable disease, LVEF ≥ 50%, who developed T resistance (defined as disease progression on T treatment with no more than 2 prior T regimens). R was administered orally at 40 mg once daily for 5 consecutive days per week. T was administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg/wk. The treatment cycle for both agents was 4 weeks. In Stage 1 of the trial, 14 patients were assessed for safety after at least 1 cycle of therapy and objective response (OR) assessed every 2 cycles according to modified RECIST guidelines. At the time of the Stage 1 interim analysis, if one or more patients exhibited an OR, study enrollment continued to a total accrual of 33 patients. Patients continued study treatment until disease progression or other discontinuation criteria were met.Results: As of June 2009, 22 patients, median age 55 years (range 33-81), were enrolled. Thirteen and 9 pts had 1 and 2 prior T regimens, respectively. Nine patients discontinued prior to the first scheduled study assessment: 6 patients for progressive disease, 1 for AE (G2 stomatitis), 1 for a protocol violation (treatment with radiation), and 1 due to death from an intestinal perforation (diagnosed at autopsy; assessed by investigator as possibly related to R). One other patient discontinued after 7 months of treatment due to elevated transaminases related to R. Twelve patients remain on treatment. There were 2 PR (1 confirmed and 1 unconfirmed) among the first 14 patients. The prospectively defined Stage 1 safety review demonstrated mostly Grade 1/2 AEs that were within the expected safety profile of either study drug. Six related Grade 3 AEs (3 stomatitis/mucositis, 1 hyperglycemia, 1 neutropenia, and 1 dysphagia) were reported. There were no study related Grade 4 AEs. Ten SAEs have been reported in 5 patients; 2 were assessed by investigators as possibly related to R (death from intestinal perforation and venous thrombosis).Conclusions: R in combination with T is feasible and well tolerated with early evidence of encouraging anti-tumor activity in T resistant HER2+ MBC. Enrollment is ongoing and updated data will be presented.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3091.
Dasatinib Plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy Data from Phase 1 Study CA180-004.
Authors: Cortes J. , Specht J. , Gradishar W. , Strauss L. , Rybicki A. , Wu X. , Vahdat L. , Paz-Ares L. , Somlo G.
Published: December 2010

Background: SRC is a potential therapeutic target in breast cancer and has a central role in hormone therapy resistance and in osteoclast activity. Dasatinib is a potent SRC inhibitor that inhibits breast cancer cell proliferation and migration in vitro, including synergy with 5FU in some cell lines, and inhibits osteoclast activity in clinical trials. CA180-004 is a phase 1 study designed to identify dose-limiting toxicities (DLT) and recommended phase 2 doses of dasatinib plus capecitabine in women with advanced breast cancer (ABC). Safety and efficacy data are now reported with additional follow-up.Methods: Cohorts of pts with ABC were treated at four dose levels (DL) with capecitabine (mg/m2 twice daily [BID] on D1-14 of 21-day cycles) and dasatinib (mg daily): DL1: capecitabine 825 + dasatinib 50 BID; DL2: capecitabine 825 + dasatinib 70 BID; DL3: capecitabine 1000 + dasatinib 70 BID; DL3a: capecitabine 1000 + dasatinib 100 once daily (QD). All pts had performance status 0-1, prior taxane and/or anthracycline and ≤2 prior chemotherapy-containing regimens for advanced disease. Disease assessments were performed every 6 weeks. DL3a was expanded for further safety and efficacy estimate using best objective response and progression-free survival (PFS) rates.Results: To date, 47 pts with ABC have been treated, 31 in escalation phase plus 16 in expansion (5 too early). Median age was 52 years (range 35-77). Tumor subtypes: 14% were Her2-amplified, 57% ER+ or PR+, 29% triple-negative. Safety was previously reported (ASCO 2009) for escalation phase; no MTD was defined based on DLTs. Of 20 evaluable pts in DL3a, 2 DLTs have been observed: 1 pneumonia, pain and pleural effusion plus 1 diarrhea, neutropenia, vomiting, mucositis and anemia. The most common drug-related adverse events (AEs, any grade) were headache, fatigue/asthenia, nausea/vomiting, diarrhea, hand-foot syndrome (HFS) and pleural effusion. The most common grade 3/4 AEs were fatigue/asthenia, HFS, vomiting and diarrhea. To date, 19 have remained on treatment ≥4 months, including 3 for >1 year. Median duration of treatment (n=42) was 13 weeks; 23 pts have discontinued for progression and 7 for toxicity. Of 38 pts with on-study assessment, 6 had confirmed partial response (treatment durations 17+, 23, 25, 36+, 71, 73 wks), 6 had unconfirmed partial or clinical response (5, 11, 13, 18, 23+, 24 wks), and 9 had prolonged stable disease (16+, 17, 23+, 24+, 25+, 29, 39+, 48+, 63+ wks). Updated efficacy data, including PFS by hormone receptor status, will be presented.Conclusions: Dasatinib and capecitabine combination treatment was well tolerated and encouraging efficacy was observed. Further assessment of this combination is warranted.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3092.
A Phase Ib Trial of RAD001, an mTOR Inhibitor, with Weekly Cisplatin and Paclitaxel in Patients with HER2-Negative Metastatic Breast Cancer.
Authors: Mayer I. , Burris H. , Bendell J. , Means-Powell J. , Arteaga C. , Shyr Y. , Pietenpol J.
Published: December 2010

Background: Pre-clinical data suggests that in basal-like breast cancers (triple-negative and some luminal B), drugs that either negatively modulate p63 and/or activate p73, such as cisplatin and paclitaxel, promote p73-dependent apoptosis. This is enhanced upon concomitant inhibition of mTOR with RAD001 (Everolimus). We conducted a phase Ib trial in patients with HER2-negative metastatic breast cancer to explore the safety, tolerability and anti-tumor activity of the combination of paclitaxel, cisplatin and RAD001.Materials and Methods: This was an open-label, phase Ib dose-escalation study. RAD001 was started at 20 mg/week on a 28-day treatment cycle, and was escalated over 3 dose levels (20, 25 and 30 mg/week). Cisplatin (25 mg/m2) and paclitaxel (80 mg/m2) doses were fixed, and were administered once a week for 3 weeks on a 28-day treatment cycle. Treatment was continued until dose-limiting toxicity (DLT) was observed or until progression of disease. All toxicities were documented using the NCI CTC v.3. Disease assessment was done every 2 months after initiation of therapy.Results: A total of 16 patients were enrolled. Median age was 55 years and the median number of previous chemotherapy regimens in the metastatic setting was 3. Seventy percent of the patients had triple-negative disease, all patients had metastatic visceral disease, and 25% of those had concomitant bone metastasis. Three patients are still on study, but have not had their first assessment of disease. Of the 13 patients that are currently evaluable for best response, 1 had a complete response (CR), 2 had partial response (PR), 7 had stable disease (SD), and 3 had disease progression (PD) at their first disease assessment. All patients with CR or PR received the higher dose level (RAD001 30 mg/week). Twelve patients have discontinued study drugs at this time; 7 due to disease progression, 3 due to toxicity and 2 due to maximum benefit. Overall median time to progression (TTP) was 5 months. The most common toxicities were alopecia (100%), neutropenia (28%), anemia (10%) and fatigue (5%). Grade 3 and 4 toxicities were overall uncommon (8.5%) and consisted of neutropenia which lasted for less than 5 days. No DLTs were seen at any of the dose levels.Discussion: The combination of weekly RAD001, cisplatin and paclitaxel was overall very well tolerated, despite neutropenia (non-dose limiting and without serious sequelae). Significant antitumor activity in this heavily pre-treated patient population was seen at all dose levels and appeared to be higher in the group treated with RAD001 30 mg/week. The recommended phase II doses for this combination are cisplatin 25 mg/m2, paclitaxel 80 mg/m2 given weekly for 3 weeks, and RAD 30 mg/week, on a 28-day treatment cycle. A phase Ib-II study of cisplatin, paclitaxel, and daily doses of RAD001 is ongoing.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3093.
A Phase Ib Trial of Erlotinib, an EGFR Inhibitor, and Everolimus (RAD001), an mTOR Inhibitor, in Patients with Metastatic Breast Cancer.
Authors: Mayer I. , Means-Powell J. , Shyr Y. , Arteaga C.
Published: December 2010

Background: The EGFR and the PI3K pathways have been implicated in breast cancer's prognosis and mechanisms of resistance to conventional therapies. Preclinical data have shown synergy between EGFR and PI3K/Akt pathway blockade. Therefore, we conducted a phase Ib trial to determine the maximum tolerated dose (MTD) and antitumor activity of Erlotinib, an oral EGFR tyrosine kinase inhibitor, and Everolimus (RAD001), an oral mTOR inhibitor, given daily to patients with metastatic breast cancer.Materials and Methods: This was an open-label, phase I dose-escalation study. Everolimus was started at 2.5 mg/d and Erlotinib was started at 100 mg/d on a 28-day treatment cycle. Doses were escalated over 6 levels (Everolimus 2.5, 5 or 10 mg daily with Erlotinib 100 or 150 mg daily). Treatment was continued until consistent dose-limiting toxicity (DLT) was observed or until progression of disease. All toxicities were documented using the NCI CTC v.3. Disease assessment was done every 2 months after initiation of therapy.Results: A total of 14 patients were enrolled on the first 2 dose levels (Erlotinib 100 mg with Everolimus 2.5 mg [level I] and 5 mg [level II] daily). Eight patients were enrolled on level I and 6 patients were enrolled on level II. The median age of all patients enrolled was 55 years of age, and 92% of them had visceral disease. Half of the patients had ER+ disease, 35% had HER2 + disease, and 15% had triple-negative disease. The median number of previous chemotherapy regimens in the metastatic setting was 4. Two patients on the level II cohort discontinued trial due to grade 3 stomatitis prior to their first disease assessment. Of the remaining 13 patients, 11 progressed at the time of their first disease assessment, and 1 patient on the dose level I cohort had a partial response that lasted for 7 months. The most common toxicities were rash (16%), transaminase elevation (15%), stomatitis (13%), fatigue (7%) and diarrhea (5%). Grade 3 and 4 toxicities were overall uncommon (3.5%), and mostly consisted of stomatitis, transaminase elevation and rash. Stomatitis was the only DLT, and was seen at dose level II. The MTD was determined to be Erlotinib 100 mg and Everolimus 2.5 mg daily.Discussion: In patients with metastatic HER2-negative breast cancer the combination of Erlotinib and Everolimus was overall well tolerated, but clinically ineffective from a tumor activity point of view in this heavily pre-treated patient population. Stomatitis was one of the most common toxicities and also the DLT in the cohort treated with dose level II. In view of the plethora of novel active agents currently in clinical trials in breast cancer, we do not believe the above combination warrants further testing in this disease.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3094.
Comparison between Nipple-Areola Saving Subcutaneous Mastectomy and Conventional Subcutaneous Mastectomy in Local Relapse and Prognosis: 5 Year Follow-Up Results.
Authors: Kang S. , Jeon Y. , Kim C. , Cho Y. , Lee S.
Published: December 2010

Backgrounds: Skin-sparing mastectomy (SSM) and the even more conservative nipple-areola-skin sparing mastectomy (NASSM) are surgical options for selected patients with indication for mastectomy. But long term result of NASSM is rare and there is no report in Korea. So, we report here 5-year follow-up results of NASSM.Materials and Methods: 202 patients who underwent SSM (N=67) or NASSM (N=135) for breast cancer at our institution between 1996 and 2006 were included in analysis. All patients were followed-up completely. For making a decision of preserving the nipple-areola complex (NAC) during operation, frozen section analysis of the retroareolar glandular tissue with precise localization was done after meticulous dissection of parenchyme under the areola. In the case of positive result in the frozen section or final histology in the NAC, NAC was sacrificed. Intra- or postoperative radiotherapy was not performed. Local relapse (LR) rate and disease free survival (DFS) was analyzed and compared the result between NASSM and SSM.Results: The mean age at diagnosis was 40.2 years old (range 24-65) and mean follow-up months of NASSM was 70.9 months and 60.5 months in SSM. 60 NACs (29.7%) of the all objective NACs were involved by cancer cell at the final histology. The cancer cell involvement to the NAC were more common in invasive carcinoma with extensive intraductal component (p<0.001) or ductal carcinoma in situ component (p=0.048). But tumor size, vascular invasion and nodal status did not affect to involvement of the cancer cell in the NAC. Local recurrences occurred in 8.9% (NASSM) and 6.0% (SSM) of all patients, but there was no significant correlation between the two procedures (p>0.05). Local recurrences occurred at NAC (8 cases), skin flap (3 cases) and chest wall (1 cases) in NASSM procedure group, and 4 skin flaps in SSM group. All NAC recurrences were treated by wide excision of NAC. After treatment of local recurrence, only one case of SSM group preceded to distant metastasis. 5 year Disease-free survival rate was 88.2% in NASSM and 88.4% in SSM group (p>0.05).Conclusion: Our long term follow-up study shows that Nipple-areola-skin sparing mastectomy is oncologically safe procedure for breast cancer in patients who are candidates for mastectomy. Even if relapse is occurred in the NAC, this recurrence cannot affect to the progression of relapse after adequate local treatment. Thus, NASSM is alternative method for SSM with oncological safety and better cosmetic outcome.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3105.
Eleven-Year Follow-Up of a Randomised Study of Pectoral Fascia Preservation after Mastectomy for Early Breast Cancer.
Authors: Dalberg K.
Published: December 2010

Background: In a previous report with 6 years follow-up a trend towards an increased risk for chest wall recurrence was seen in breast cancer patients operated with preserved pectoral fascia compared to removal of the pectoral fascia. The aim of the present study was to assess whether the preservation or removal of the pectoral fascia in the modified radical mastectomy procedure had any impact on survival or local control in breast cancer patients when followed long term.Method: The trial included 247 patients with breast cancer who underwent modified radical mastectomy in five Swedish hospitals 1993-1997. The median follow-up time was 11 years. The patients were randomised between removal (n=122) versus preservation (n=125) of the pectoral fascia.Results: The breast cancer specific survival at 10 years was 75%. Removal or preservation of the pectoral fascia had not any significant impact on the chest-wall recurrence and on breast cancer specific survival. A total of 18 patients with chest-wall recurrence were seen in the group allocated to pectoral fascia preservation versus 10 in patients allocated to pectoral fascia removal (hazard ratio=1.8, 95%CI = 0.8-4.0). The majority of the chest-wall recurrences were detected 0-5 years postoperatively. The cumulative chest-wall recurrence rates at 5 and at 10 years were 13 and 15% respectively in patients allocated to pectoral fascia preservation and 8 and 9% in patients allocated to pectoral fascia removalConclusion: Neither the chest-wall recurrence rate nor the breast cancer specific survival is significantly influenced by the preservation of the pectoral fascia when the tumor macroscopically does not involve the muscle.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3109.
Assessment of the Likelihood of Invasive Breast Cancer When Core Needle Biopsy Shows DCIS.
Authors: Kurniawan E. , Rose A. , Mou A. , Buchanan M. , Collins J. , Wong M. , Miller J. , Mann G.
Published: December 2010

Background: Ductal carcinoma in-situ (DCIS) on core needle biopsy (CNB) may be associated with a final diagnosis of invasive cancer (IC). As patients with IC need axillary assessment, those at risk of upstaging may be appropriate for sentinel node biopsy (SNB) at initial surgery, preventing the need for re-operation. We assessed this risk using pre-operative factors to develop a management algorithm.Materials and Methods: All patients whose CNB showed DCIS or DCIS with microinvasion (DCISm) from a single population-based breast screening program in Australia between 1994 and 2006 were studied. Medical records were reviewed for demographic, radiologic, clinical and pathologic data.Results: 11 of 15 DCISm cases (73.3%) and 65 of 375 DCIS cases (17.3%) were upstaged to IC. Microinvasion on CNB overwhelmingly predicted presence of frank invasive cancer. For cases of DCIS, multivariate analysis showed that (1) palpability (p=0.009), (2) large mammographic size ≥20mm (p=0.001) and (3) prolonged screening interval ≥3 years (p=0.008) were associated with upstaging. On univariate analysis, (4) non-calcific mammographic features (mass, architectural distortion or non-specific density) were significantly associated with upstaging (p=0.001). There was a trend towards upstaging in patients with high grade DCIS on CNB (p=0.07). Factors not associated with upstaging were microcalcifications (p=0.12), comedonecrosis (p=0.14), age (p=0.38) and CNB method (p=0.50). The rate of upstaging increases with the number of associated risk factors present in a patient: 8.3% in patients with no risk factors, 21.2% in those with one risk factor, 38.6% in those with two risk factors, and 52.9% in those with three risk factors. 13 patients (3.3%) had lymph node metastases.Conclusions: The risk of upstaging can be estimated using pre-operative features in patients with DCIS on CNB. We propose a management algorithm that includes SNB for DCIS patients: with microinvasion on core biopsy, with two or more predictive factors, and those with planned total mastectomy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3111.
Impact of Primary Site Surgical Resection on Survival in Stage IV Breast Cancer.
Authors: Ahn S. , Han W. , Min J. , Bae J. , Ko E. , Yu J. , Noh D.
Published: December 2010

Background: Currently, primary treatments for stage IV breast cancer are radiation and systemic therapy which include chemotherapy, endocrine therapy and targeted therapy. Surgical resection of primary tumor is usually done for tumor-related complications. A recent review suggested that surgery may improve long-term survival in stageIV breast cancer patients. We evaluated the impact of primary site surgical resection on survival in such patients.Material and Methods: We reviewed the records of stage IV breast cancer patients treated at Seoul National University Hospital between 1992 and 2008. Clinical and tumor characteristics, systemic and local treatments were compared for the surgically versus nonsurgically treated patients.Results: Of 199 patients identified, 111(55.8%) recevied surgical excision of their primary tumor and 88(44.2%) did not. The mean survival of surgically treated patients was 67 months versus 52 months for patients those who did not(p=0.0276). In multivariate analysis, after adjustment for ER status, visceral metastasis, number of metastatic sites and herceptin treatment, surgery remained an independent factor associated with improved survival(HR 0.547[95%CI 0.359-0.971] p=0.001).Discussion: Surgical resection of the primary tumor in stage IV breast cancer patient was independently associated with improved survival, even after adjustment for other factors associated with survival. Randomized prospective trials are needed to validate these findings.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3117.
Does Having Primary Breast Reconstruction Influence Chest-Wall Radiotherapy Rates?
Authors: Agusti A. , Rusby J. , Sundaramorthy S. , Roche N. , Gui G. , Harris P. , James S. , Ross G. , MacNeill F.
Published: December 2010

BACKGROUND: Immediate breast reconstuction should be discussed with all patient's who require mastectomy. The immediate recontruction may interfere with postmactectomy chest wall radiotherapy (RT) .The adverse impact of chest-wall radiotherapy on the reconstructed breast is widely reported. Predicting who will require chest-wall RT prior to surgery can be difficult, limited to the knowledge of full pathological staging and often only known after mastectomy. Does having primary reconstruction influence in chest-wall RT decision making? Are women who opt for primary reconstruction less likely to receive RT than those who choose no reconstruction?METHODS: From 1st Jan 2008 to 31st March 2009, we performed 430 mastectomies 226 were mastectomy only (M0), 204 were mastectomy with immediate reconstruction (MIR). Data were prospectively recorded on chest wall recurrence risk adjuvant chest wall radiotherapy, type of breast reconstruction (tissue expander, fixed volume implant, autologous reconstruction only and autologous reconstruction implant assisted).Chest-wall recurrence risk was calculated from pathology.RESULTS:Performed 430 mastectomies, 335 for invasive disease, 53 for DCIS, 6 for ALH/LCIS, 36 benign (for risk reduction or symmetry purposes).Two hundred and twenty-six (52%) were mastectomy only (M0), 204 (48%) were mastectomy with immediate reconstruction (MIR).Chest wall radiotherapy + MO vs. MIRTotal RT 130(30%), of which 88 (67%, 88/130) and 44 (33%, 44/130) were MO and MIR respectively. MOMO+RTMIRMIR+RTLow Risk (ASCO pN-ve/T<50mm)42 (18%,42/226)4 (9%,4/42)44 (21%,44/204)2 (4%,2/44)Moderate Risk (SUPREMO pN+ (1-3) and/or pT2)89 (39%)31 (34%,31/89)59 (29%)23 (39%,23/59)High Risk (ASCO pT_>50mm and/or pN+_> 4)77 (32%)53 (73%,53/77)29 (14%)19(65%,19/29) RT and Type of Reconstruction: Of the 204 MIR, 85 (42%) were autologous and 119 (58%) implant based of which 16 autologous (18%,16/85) and 30 (25%,30/119 ) implants received RT.CONCLUSION:Chest wall RT rates are broadly comparable across the three risk groups for MIR and MO suggesting MIR doesn't influence decision making regarding RT.The number of high risk MIR was small (14%) suggesting successful preoperative selection.Slightly higher radiotherapy rate for implant based reconstruction may be explained by staged reconstruction.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3119.
Oncoplastic Surgery Using Laparoscopically Harvested Omental Flap: Results of 100 Patients.
Authors: Zaha H.
Published: December 2010

Background: Indication of breast-conservation treatment (BCT) has been increased due to various oncoplastic techniques. The latissimus dorsi flap is one of the most commonly used techniques for partial breast reconstruction. The disadvantage of this technique is the presence of donor-site morbidity and deformity. Laparoscopically harvested omental flap (LHOF) may compensate for these disadvantages associated with the donor-site. The aim of this study was to access the safety and the efficacy of this procedure.Methods: Oncoplastic surgery using LHOF was applied to 100 patients who underwent either BCT or nipple-sparing mastectomy (NSM) between April 2002 and March 2009. The patients who underwent BCT had a large loss of breast tissue (more than 30% of breast tissue), and LHOFs were applied for partial breast reconstruction. All of omental flaps was laparoscopically harvested. The pedicled flap was extracted via a small subcutaneous tunnel created from the xiphoid process, and filled the dead space of a breast. Free flap was withdrawn from a small incision in the lower abdominal wall. Then microanastomoses between right gastroepiploic vessels and thracodorsal vessels were performed. The patients were followed-up for complications and cosmetic results.Results: 65 cases of BCT and 35 cases of NSM were included. The omental flaps were successfully harvested in 99 cases without conversion to open surgery (99%). Median operative time for harvesting the omental flap was approximately 1 hour. Morbidity associated with laparoscopy occurred in 8 cases (8%), which were 5 partial graft necroses, 2 vascular injuries of the gastroepiploic artery and one incisional hernia. Morbidities not associated with laparoscopy occurred in 9 cases (9%), which were two postoperative hematoma, 3 wound infections and 4 others. Cosmetic results were almost satisfactory, with a soft breast that was natural in appearance. Postoperative radiotherapy did not change the cosmetic outcome. Donor-site scars were minimal like those of laparoscopic cholecystectomy. However, in 17 patients (17%), the amount of omentum was found to be inadequate when applied for reconstruction after NSM. In 19 patients (19%), minor deformity or asymmetry of the reconstructed breast had occurred because of postoperative infectious complications or volume lack.Conclusion: Although there is a limit of volume, LHOF is safe procedure with minimal donor-site morbidity and deformity, and attractive autologous flap for partial breast reconstruction.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3120.
Notch-1 Confers Resistance to ErbB-2 Targeted Inhibition by Regulating PTEN, p27, and IGF-1R.
Authors: Mehta K. , Meeke K. , Clementz A. , Albain K. , Osipo C.
Published: December 2010

Background: Amplification, over-expression, and/or hyperactivity of ErbB-2 occur in 30% of breast tumors. Metastatic breast tumors that overexpress ErbB-2 are difficult to treat and generally resistant to trastuzumab or lapatinib. We have recently published that overexpression of ErbB-2 suppresses Notch-1 activity and this is reversed by inhibitors of ErbB-2, trastuzumab or a tyrosine kinase inhibitor (Osipo et al., 2008. Oncogene). Furthermore, we demonstrated that trastuzumab resistance is reversed when Notch-1 is downregulated by siRNA or when cells are treated with a gamma-secretase inhibitor. Overexpression of IGF-1R and/or downregulation of PTEN, and p27Kip1 have been shown to be very sensitive markers of trastuzumab resistance. Based on our results and what is known from the literature, we asked by what mechanism Notch-1 contributes to trastuzumab resistance and can a combination therapy prevent or reverse the resistant phenotype by using a pre-clinical in vivo model.Methods: Using a pcDNA3.1-NIC construct expressing activated Notch-1 and a Notch-1 siRNA, we either increased NIC levels in trastuzumab sensitive or downregulated Notch-1 in trastuzumab resistant BT474 cells, respectively and measured protein and mRNA expressions of PTEN, p27Kip1, and the IGF-1R. In addition, BT474 breast tumor xenografts were generated in athymic mice and randomized to vehicle, MRK-003 or Ly411,575 gamma-secretase inhibitor, trastuzumab, or trastuzumab plus a gamma-secretase inhibitor. Tumor size was measured up to 14 weeks with treatments and up to 12 weeks after stopping treatments.Results: The results showed that intracellular, active Notch-1 (ICN) increased mRNA and protein expression of the IGF-1R, while simultaneously decreased protein expressions of PTEN and p27Kip1 in ErbB-2 positive breast cancer cells sensitive to trastuzumab. Conversely, knockdown of Notch-1 by siRNA in resistant cells decreased IGF-1R, while increasing PTEN and p27Kip1. The xenograft studies demonstrated that combining a GSI with trastuzumab either completely prevented tumor recurrence (MRK-003 GSI) or significantly delayed tumor recurrence (Ly 411,575 GSI).Conclusions: Taken together, these results suggest that Notch-1 potentially contributes to trastuzumab resistance by upregulating the IGF-1R and downregulating PTEN and p27Kip1 in vitro. The benefit of inhibiting Notch activity using a GSI in combination with trastuzumab is prevention of resistance and tumor recurrence.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3123.
Potential Benefit of an Agonistic Anti IGFIR Antibody (scFv-Fc) as an Effective Breast Cancer Therapy.
Authors: Zhang X. , Yee D.
Published: December 2010

Multiple monoclonal antibodies targeting the type-1 insulin-like growth factor receptor (IGFIR) are currently in different phases of clinical trials. All the reported antibodies inhibit biochemical activation of IGFIR and block cell proliferation. In contrast, we have reported an agonistic anti-IGFIR antibody scFv-Fc that stimulates IGFIR and its downstream signaling of PI3K and MAPK pathways to promote cell proliferation in vitro. Like the purely antagonistic antibodies, our previous work has shown that scFv-Fc can down regulate IGFIR levels, partially inhibit xenograft growth of MCF-7 cells in athymic mice, and render MCF-7 cells refractory to the mitogenic effects of IGF-I after the initial wave of agonistic activity. MCF-7 cells maintained long term in scFv-Fc have low levels of IGFIR expression, yet the remaining receptor is activated and inhibited by an IGFIR tyrosine kinase inhibitor (TKI) AEW541. In this study, we have further explored the future potential of using this antibody as breast cancer therapy. The common characteristic effect of anti-IGFIR antibodies is to down regulate IGFIR. Since scFv-Fc can activate IGFIR signaling in a manner different than the natural ligand IGF-I, we examined if this antibody could render cells more sensitive to TKI. In MCF-7 cells, IC50 of the IGF1R tyrosine kinase inhibitor AEW541 was decreased 5 to 10 fold when cultured in scFv-Fc. ER negative MDA-MB-231 cells are insensitive to both inhibitory antibody (AVE1642) and TKI (AEW541) in the presence or absence of IGF-I, which may due to the very low levels of IGF1R that are weakly activated by IGF-I. MDA-MB-231 cells were not affected by AEW541 in monolayer growth assays. After chronic treatment of MDA-MB-231 with scFv-Fc for 2 months, AEW541 significantly inhibited monolayer cell growth by 30% in the presence or absence of IGF-I. We also examined the effect of scFv-Fc's effect on AEW541 inhibition of cell motility in MDA-MB-231 cells. Both acute and chronic treatment of scFv-Fc dramatically inhibited cell migration by 90%.Inhibitory antibodies AVE 1642 and MK 0646 had no effect on cell migration. Both IGF-I and excess amounts of AVE 1642/MK 0646 did not reverse scFv-Fc inhibition on cell migration, suggesting other cell signaling system may be involved. In MDA231-BO, a metastatic variant of MDA-MB-231, scFv-Fc had less inhibitory effect on basal cell migration, but in combination of AEW541 treatment, cell migration was significantly decreased by 70%. In conclusion, our data suggests an antibody with agonistic activity may have different properties than purely inhibitory antibodies. Specifically, initiating biochemical signaling followed by inhibition of tyrosine kinase activity and receptor downregulation may be a potent way to disrupt IGF mediated breast cancer cell biology.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3125.