bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-09-20: Response Prediction to Neoadjuvant Chemotherapy: Comparison between Pre-Therapeutic Gene Expression Profiles and In Vitro Chemosensitivity Assay
Authors: Singer CF , Klinglmueller F , Staudigl C , Fink-Retter A , Gschwantlerkaulich D , Helmy S , Pfeiler G , Dressler A-C , Sartori C , Bilban M.
Published: April 2011

Purpose: Although the use of (neo-)adjuvant chemotherapy in breast cancer patients has resulted in improved disease-free and overall survival, not all patients benefit equally. Nevertheless, chemotherapy is still applied empirically, since clinical tests for response prediction are not routinely available. We have evaluated the utility of an in vitro chemosensitivity assay (ATP-TCA) in predicting response to neoadjuvant chemotherapy. Methods: Pre-therapeutic tumor core biopsies were obtained from 65 breast cancer patients and subjected to a standardized ATP-based Epi/Doc tumor chemosensitivity assay (ATP-TCA). Of these, 30 breast cancer patients were also assigned to three cycles of neoadjuvant epirubicin 75 mg/m2 and docetaxel 75 mg/m2 (Epi/Doc) in a prospectively randomized clinical trial. Tumor response was evaluated by pre-and post-interventional ultrasound measurements of tumor diameter, and by differential Ki67 expression. Results: 3 Cycles of neoadjuvant Epi/Doc resulted in a clinical response according to RECIST criteria in 11/23 evaluable patients (48%), and in a profound reduction in tumor proliferation in 10/23 patients (43%). Similarly, in vitro treatment of tumor cell suspensions with Epi/Doc performed in 65 pre-treatment core-biopsies yielded chemosensitivity in comparable fraction of patients (30/65, 46%). When the differentail changes in tumor cell proliferation in response to 3 cycles Epi/Doc in 23 patients were compared with ATP-TCA results obtained from the pre-interventional tumor core-biopsies of the same individual patients, we found that the efficacy of Epi/Doc in vitro was significantly correlated with differential changes in tumor cell proliferation in response to 3 cycles Epi/Doc in vivo (p= 0.0011; r=0.73670, Spearman's rho), but did not predict for changes in tumor size when measured by ultrasound. Conclusion: This is the first prospective clinical trial to demonstrate the utility of a standardized in vitro chemosensitivity assay in predicting the individual response to chemotherapy in breast cancer patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-20.
Abstract P2-09-23: Investigating VAV3 Expression as a Novel Biomarker and Indicator of Chemosensitivity in Basal-Like Breast Cancer
Authors: Getz JE , Anderson EM , Balagurunathan Y , Black MA , Hedenfalk IA , Willis AL , Ramos P , Mancini CM , Cunliffe HE.
Published: April 2011

Background: Basal-like breast (BLB) cancer accounts for ∼15% of all breast cancers diagnosed. Patients with BLB cancer are typically younger, present with higher tumor grade and despite recent advances in therapy, still have a poor outcome. BLB cancers are the most proliferative breast tumor sub-type, are commonly triple-negative (ER-, PgR-, HER2/neu-), and often harbor mutations in TP53 and BRCA1. The biological drivers of disease progression in this tumor subtype remains poorly understood. Recently, VAV3, a guanine nucleotide exchange factor and a member of the of the Rho/Rac/Cdc42 GTPase superfamily, has been reported as overexpressed and oncogenic in ER+ breast cancer cells. Our preliminary studies using publicly available microarray data indicates a consistent lack of VAV3 in BLB cancer, particularly those patients with shorter survival time following chemotherapy. We therefore hypothesize that VAV3 is a novel biomarker of BLB cancer and potential predictor of chemosensitivity in this subtype.

Materials and Methods: Gene expression microarray technology, qRTPCR and western blotting was used to investigate relative expression of VAV3 in a panel of breast cancer cell lines and tumors. Array Comparative Genomic Hybridization and Fluorescence in Situ Hybridization were used to evaluate VAV3 gene copy number. BLB cancer cell lines stably overexpressing VAV3 were developed to evaluate the role of VAV3 in sensitivity to chemotherapy.

Results: Unsupervised hierarchical clustering revealed low VAV3 expression in BLB tumors compared to all other intrinsic subtypes. Consistently lower VAV3 mRNA and protein expression were observed in BLB cancer cell lines compared to luminal epithelial cell lines, consistent with our in silico observations. We confirmed that low VAV3 expression in the BLB cancer cell lines is not due to gene copy number loss. Ectopic expression of VAV3 in MDA-MB-231 BLB cancer cells significantly enhanced their sensitivity to cisplatin.

Discussion: A consistent lack of VAV3 gene expression is evident in BLB tumors, however the mechanism underlying this loss is yet to be elucidated. Our findings support a hypothesis that low VAV3 expression is a potential diagnostic biomarker of BLB cancer, and that VAV3 expression may be a predictor of response to chemotherapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-23.
Abstract P2-09-26: Circadian Clock Genes in Primary Breast Cancer: Strong Predictors of Pathologic Response on Neoadjuvant Chemotherapy
Authors: Iurisci I , Valet F , Giacchetti S , Pierga JY , André F , De Cremoux P , Asselain B , Delaloge S , de Thé H , Spyratos F , Brain E , Sigal-Zifrani B , Mignot L , Marty M , Levi F.
Published: April 2011

Background: Circadian clocks involve 15 specific genes, which control cell cycle, apoptosis, DNA repair and metabolism. Circadian disruption is associated with both an increased risk of breast cancer, and poor survival in patients (pts) with metastatic cancer (IARC#98; Innominato et al. Cancer Res 2009).

Objective: to provide first evidence of clinical relevance of clock genes expression for the therapeutic sensitivity of primary breast cancer. Method: Affymetrix Hgu133plus2 microarrays data were derived from 189 primary breast cancers. All the pts had non metastatic disease and were registered in multicenter Phase II trial of neoadjuvant chemotherapy with epirubicin-cyclophosphamide (4 courses) then docetaxel ± herceptin (4 courses). In this study, negative hormonal receptor status and limited tumor size predicted for pathological complete response rate (pCR) (Pierga JY, et al Breast Cancer Res Treat. 2010).The expression data of 15 core clock genes, within the whole tumor transcriptome, were related both to tumor mitotic index (MI) and estrogen receptors (ESR1), and to chemotherapy-induced pCR. Statistical validation involved T-test statistics, with corrections for multiple testing.

Results:

In the tumor biopsy obtained before treatment onset, both Per2 and Cry2 expressions correlated positively with ESR1 (r≥0.43; P<0.001) and inversely with (MI (r≤−0.28; P<0.007). In addition, a positive correlation was found for Dec 1 with ESR1 (r=0.65, P<0.001). The mean expressions of Per2, Cry2 and Dec 1 before chemotherapy were lower in the 32 pts who subsequently achieved pathologic complete response (pCR) as compared to the 157 who did not (P<0.001). No other clock gene expression was significantly related to pCR. The odds ratio confirmed the decreased chance of achieving pCR with increased expression of clock genes Per2, Cry2 or Dec1.

Clock gene expression and pCR

Conclusion: Low expressions of three core genes in the negative loop of the molecular circadian clock strongly predicted for the induction of a pathologic complete response of primary breast cancer with neoadjuvant chemotherapy. While circadian clock disruption seems to constitute a poor prognostic factor in cancer patients, our data suggest that the downregulation of core circadian genes in tumors significantly enhances susceptibility to chemotherapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-26.
Abstract P2-09-35: Differential Pathologic Response from Primary Systemic Chemotherapy across Breast Cancer Intrinsic Subtypes
Authors: Jinno H , Matsuda S , Takahashi M , Hayashida T , Sakata M , Mukai M , Kitagawa Y.
Published: April 2011

Purpose: This study's purpose was to evaluate the clinical utility of breast cancer intrinsic subtypes in the prediction of pathological complete response (pCR) in a cohort of breast cancer patients receiving primary systemic chemotherapy.

Patients and Methods: Patients with stage II/III breast cancer received 4 cycles of XT (capecitabine 1650 mg/m2 on days 1-14 and docetaxel 60 mg/m2 on day 8 every 3 weeks), followed by 4 cycles of FEC (fluorouracil 500 mg/m2, epirubicin 90 mg/m2, cyclophosphamide 500 mg/m2 on day 1 every 3 weeks). Immunohistochemical analysis of estrogen receptor (ER), progesterone receptor (PgR), HER2, epidermal growth factor receptor (EGFR), cytokeratin (ck) 5/6, and Ki67 was performed in core needle biopsy samples at baseline. Tumors were classified as luminal A (ER+ and/or PgR+, and Ki67<20%), luminal B(ER+ and PgR+, and Ki67≥20%), luminal-HER2 (ER+ and/or PgR+, and HER2+), HER2-enriched (ER-PgR-, and HER2+), or triple-negative (ER-, PgR-, and HER2-). Triple-negative tumors with and without EGFR+ and/or ck 5/6+ were further classified as basal-like and non-basal-like TN (NBTN), respectively. pCR was defined as no microscopic evidence of residual viable tumor cells, invasive or noninvasive, in all resected specimens of the breast. Results: Twenty-six (31.3%) patients were classified as luminal A, 12 (14.5%) were luminal B, 15 (18.1%) were luminal-HER2, 9 (10.8%) were HER2, 10 (12.0%) were basal-like, and 11 (13.3%) were NBTN. The overall response rate was 90.4%, including a complete response in 30 patients and a partial response in 45 patients. The overall pCR rate was 15.5% (12/83). The highest pCR rate (40.0%) was observed in patients with basal-like tumors. In triple-negative patients, basal-like patients showed significantly higher pCR rate than NBTN patients (40.0% vs. 9.1%, p=0.01). There were no cases with pCR in a cohort of luminal-HER2 subtype patients. A higher proportion of luminal B patients had pCR than luminal A patients (25.0% vs. 3.8%, p=0.01). With 33 months median follow-up, estimated 2-year disease-free survival for luminal A, luminal B, luminal-HER2, HER2, basal-like, and NBTN was 80.8%, 83.3%, 66.7%, 88.9%, 80.0%, and 81.8%, respectively.

Conclusions: Our data indicate that breast cancer subtypes are useful predictive biomarkers of pCR in breast cancer patients treated with primary systemic chemotherapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-35.
Abstract P2-10-06: Identification and Referral of Appropriate Patients for Genetic Services in the Community Setting: An innovative Approach
Authors: Sutphen R , Steenblock K , Carmany E , Trivedi A , Lewis K.
Published: April 2011

Although the U.S. Preventative Services Task Force, the HHS's Healthy People 2020 draft objectives and multiple professional medical societies recommend genetic counseling as the standard of care for women with family history suggesting increased risk for breast cancer, there is clear evidence that this standard is not being achieved. On the one hand, many women who are appropriate for genetic counseling are not receiving it, while on the other, many individuals are inappropriately undergoing BRCA testing. A number of factors have been identified as contributors to these poor public health outcomes, including lack of physician proficiency in genetics and lack of availability of genetic counseling services due to limited number of trained genetics professionals and their limited geographic distribution.

We report a novel systematic approach implemented through a large regional health plan (approximately 500,000 members, 14,000 network providers, 112 commercial hospitals, and 58 medicare hospitals) to address these issues, and present data regarding its performance. Components of the program include: 1) implementation of a model BRCA coverage policy that follows USPSTF guidelines recommending genetic counseling, 2) increased access to genetic counseling via telephone delivery and 3) removal of financial, language, convenience and other barriers to genetic counseling services.

The program was implemented in January, 2010 and data will be presented for January through September. Specific results include 1) changes in volume of BRCA testing (including by provider specialty), 2) decrease in rates of inappropriate BRCA test requests (i.e., requests not meeting national guidelines/clinical criteria for testing), 3) discrepancies in reported family history based on methods of data collection, 4) increased awareness and dissemination of genetic services in the community setting, and 5) cost-effectiveness estimates. This program may serve as a model for appropriate translation of genetic testing into public health benefit.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-10-06.
Abstract P2-12-01: Is Cancer-Specific Distress Correlated with Time to Definitive Surgery in Breast Cancer Patients?
Authors: Daup MB , Lush EL , Dedert E , McMasters KM , Sephton SE , Chagpar AB.
Published: April 2011

INTRODUCTION: A number of studies have investigated factors influencing delay in seeking medical care for self-detected breast symptoms. Few, however, have sought to understand factors that are correlated with the time interval between diagnostic imaging and definitive surgery. We sought to determine factors that may influence this time interval. METHODS: From May 2005 to January 2009, a prospective study of 59 breast cancer patients was performed in which patients’ cancer-related distress was evaluated using the Impact of Events Scale (IES). After patients undergoing neoadjuvant chemotherapy and those who did not have imaging or surgery were excluded, the remaining 43 patients formed the cohort of interest for this analysis. The effect of clinicopathologic and psychological factors on the time between diagnostic imaging and definitive surgery was evaluated using non-parametric statistics (SPSS, Version 18.0).

RESULTS: The median time between diagnostic imaging and definitive surgery in this cohort was 43 days (range; 4-200). In 25 patients (58.1%), this interval was less than 45 days. Patient age, largest tumor size on imaging, and previous history of breast or other cancers did not appear to be related to time to surgery. Similarly, race, marital status, education, income and insurance status were not significant predictors of time to surgery. Patients who had a longer time interval between imaging and surgery scored higher on the avoidance and total distress subscales of the IES (median 19.5 vs. 12.0, p=0.016 and 37.0 vs. 29.0, p=0.028, respectively). In particular, patients with a longer time between imaging and surgery were more likely to report that they “tried not to think about it” (p= 0.040), “tried not to talk about it” (p=0.039) and “stayed away from reminders of it” (p=0.001).

CONCLUSION: Psychological distress associated with a diagnosis of cancer is significantly correlated with the time to definitive surgery in breast cancer patients. Avoidance behaviors tend to be associated with a delay in surgery. Early psychosocial support aimed at reducing such distress may shorten time to definitive treatment in such patients; alternatively, shorter times to surgery may reduce cancer-specific distress.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-12-01.
Abstract P2-13-03: Osteonecrosis of the Jaw: Dental Outcomes in Metastatic Breast Cancer Patients Treated with Bisphosphonates with/without Bevacizumab at Roswell Park Cancer Institute
Authors: Ngamphaiboon N , Frustino JL , Kossoff EB , Sullivan MA , O'Connor TL.
Published: April 2011

Background: The etiology, optimal management, and long term outcome of osteonecrosis of the jaw (ONJ) is not well understood. Large trials have suggested that the combination of bevacizumab and bisphosphonates (BPs) does not significantly increase the incidence of ONJ. Because healing after mucosal trauma or dental surgery requires revascularization, it is possible that bevacizumab use could influence dental outcomes. Theoretically, the combination of bevacizumab and BPs may affect the time to development of ONJ and/or the response to dental therapy. Dental management of ONJ has not changed over time in our center, but increased recognition and screening may impact the dental outcome.

Methods: We reviewed all cases of ONJ in metastatic breast cancer patients treated with BPs and with or without bevacizumab at Roswell Park Cancer Institute between October 2002 and April 2010. All patients diagnosed with ONJ discontinued BP therapy, while 3/7 (42%) continued bevacizumab until breast cancer progression. Type of BP, duration of treatment, total dose of BPs and bevacizumab dosing were recorded. All patients were treated in the department of dentistry with a combination of antibiotics, debridement, and chlorhexidine scrub. We evaluated the time to diagnosis of ONJ after the initiation of BP therapy, total dose of BP and dental treatment outcomes. Statistical analysis was performed using t-test and log-rank analysis. Results: See tables. 27 ONJ patients with a median age of 57 years (range 40-68) were analyzed. Patients were treated with zoledronic acid (95%), pamidronate (20%), or both (15%). 2 patients were excluded from dental response analysis due to lost follow up. Overall median time to ONJ treatment response was 5.0 months (range 1.3-67.5). Conclusions: The addition of bevacizumab to BP treatment did not significantly alter the time to the development of ONJ, the number of BP doses administered prior to diagnosis, or the response to dental treatment. However, ONJ response rates (complete and partial) to dental therapy have improved from 38% prior to 2007 to 58% after 2007, likely reflecting improved recognition and earlier treatment.

Table.1 Time to ONJ and number of BP doses

Table 2 ONJ response to dental treatments

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-13-03.
Abstract P2-14-01: A Prospective Controlled Analysis of Fertility Preservation by Oocyte and Embryo Cryopreservation Using an Aromatase Inhibitor-Gonadotropin Protocol: Treatment Outcomes and Safety in Young Women with Breast Cancer
Authors: Oktay K , Lee SH , Moy F
Published: April 2011

Objective: Breast Cancer (BCa) is the most common malignancy in reproductive age women and letrozole, an aromatase inhibitor, has been used to reduce estrogen exposure in women undergoing embryo/oocyte cryopreservation prior to chemotherapy. Our aim was to determine the long-term outcomes and safety of letrozole-FSH protocol. Design: Prospective

Materials and Methods: Women with stage 0-3 BCa underwent ovarian stimulation with letrozole 5-mg starting menstrual cycle day (CD)-2 and gonadotropins 150-450 IU, starting CD-4. Oocyte maturation was triggered either with human chorionic gonadotropin (hCG) or a Gonadoropin Releasing Hormone Agonist (GnRHa).

Results: Of the 129 women with mean age of 35.2±4.6, 13 vs. 91 underwent oocyte vs. embryo freezing, and 9 underwent both. Ovarian trigger with GnRHa (n=37/115, 32.2%) resulted in higher number of mature oocytes (10.9±6.6 vs. 8.4±6.0, p=0.045,). Of those, 21 underwent 25 frozen embryo transfers (mean age 35.5±4.5) with a clinical pregnancy (CP) rate of 68% and y per ET. CP rates were similar between the self-transfer and gestational carrier groups (7/9 vs. 10/16, p=0.37). No birth defects are encountered. Relapse rates were compared to a similar group of women with BCa (n=141, mean age 35.7±4.7, similar projected 10-year relapse rate at the outset by! adjuvant online) who elected to not to undergo ovarian stimulation. After a mean follow up of 2.4±1.6 vs. 2.9±1.7 years (range 8 mo - 5.6y vs. 4m-6.8y) women who had undergone ovarian stimulation with letrozole and FSH had a significantly lower recurrence rate [2.0% vs. 25.0%, Hazard ratio 0.08, 95%C.I. (0.06, 0.48), p=0.01]. Conclusions: This long term follow up of LF protocol for up to 7 years indicates that the protocol is safe, efficient and is associated with age-appropriate pregnancy success rates. Whether pretreatment with letrozole improves BCa treatment outcomes should be further investigated. Women with BCa can be safely offered this protocol when undergoing fertility preservation prior to chemotherapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-01.
Abstract P2-14-02: A Pilot Study of Vascular Endothelial Growth Factor Inhibition with Pazopanib in Patients (pts) with Lymphedema Following Breast Cancer Treatment
Authors: Miller KD , Brown C , Perkins SM , Schneider BP , Storniolo A , Sledge GW.
Published: April 2011

Purpose: Lymphedema is a significant long-term complication of primary therapy for breast cancer. VEGF has a major impact on vascular permeability and lymphangiogenesis. In a prior case control study, we found a significant increase in serum VEGF-C (median 6895 vs. 5349 pg/mL, p=0.0016) in women with lymphedema compared to women without lymphedema suggesting inhibition of VEGF-C as a potential therapeutic strategy.

Methods: Pts with significant unilateral lymphedema were treated with pazopanib 800 mg/day continuously. Baseline assessments include arm volume, interstitial fluid pressure (IFP), extracellular fluid volume by lymphometer (ECF), quality of life (QOL) and plasma VEGF-C,-D, and R3. IFP was measured serially for 24 hours after the first treatment; arm volume, ECF, QOL, and plasma VEGF-C/D/R3 are assessed every 4 weeks.

Results: Ten pts were enrolled. Median duration of lymphedema was 3.5 years (0.7-8.2) Median time since surgery was 5.1 years (1.0-14.2); median time since radiation (n=9) was 4.7 years (0.4-8.8). Complete IFP data are available in 7 pts. Baseline IFP was significantly higher in the affected compared to unaffected arm (mean 5.73 vs. -1.78 mmHg; p=0.0005). Mean IFP in the affected arm decreased an average of 76% 24 hours after initiation of pazopanib (5.73 vs. 1.56 mmHg; p=0.0061). Toxicity was greater than anticipated with grade 3 fatigue (n=3), arthralgia (n=2), and anorexia (n=1); three pts discontinued therapy prior to the first post-treatment assessment. Five pts met the definition of response with a ≥25% reduction in excess arm volume four weeks after initiating treatment. ECF significantly (p=0.014) decreased as well though the mean difference in excess arm volume did not significantly change (p=0.06). Conclusions: Preliminary data supports the hypothesis that VEGF plays a role in the development and/or persistence of lymphedema after local therapy for breast cancer. Pazopanib acutely decreases IFP, leading to a decrease in ECF and modest improvement in arm volume but results in significant toxicity at the dose used on this study. Subsequent studies will explore a lower dose of pazopanib in this population. This study was supported by the Breast Cancer Research Foundation with pazopanib supplied by GSK.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-02.
Abstract P2-14-07: Predictors of Employment Outcomes in Breast Cancer (BrCa) Patients: An Analysis from E2Z02 (ECOG's SOAPP Study)
Authors: Tevaarwerk AJ , Lee J-w , Sesto MC , Cleeland CS , Wagner LI , Chang VTS , Fisch M.
Published: April 2011

Cancer survivors are more likely to be unemployed than healthy counterparts (de Boer et al, JAMA 2009). BrCa patients comprise roughly one-fourth of the survivor population and face challenges in their ability to work. Age and cancer therapy may increase the risk for unemployment (Hassett et al, Cancer 2009). We analyzed data from E2Z02 to examine factors affecting employment in BrCa patients.

Methods: E2Z02 prospectively enrolled patients with breast, colon, lung and prostate cancer irrespective of therapy or stage. We limited this analysis to white or black BrCa patients with age at registration ≥65 yrs (those over 65 were excluded as likely to be retired; other minorities were excluded due to small numbers). Patients and oncologists answered the MDASI-ECOG regarding symptoms; additional baseline data regarding disease and treatment were collected. Change in employment was assessed by “Has your employment status changed due to illness?’ [Answer = Yes/No]; and level of employment by “What is your current employment status?” [Answer = full-time; part-time; not in the workforce]. We developed a multivariate logistic regression model for each employment outcome (change in employment, level of employment). Explanatory variables included treatment number (TNs), age (≥45 vs 46-65 yrs), race (white vs black), stage (nonmetastatic vs metastatic), therapy status (off vs on), and ECOG PS (0 vs 1 vs 2-4). TNs were counted as 0 (no medical therapy [MT] or radiotherapy [RT]), 1 (either) or 2 (both). MT encompassed both hormone and chemotherapy.

Results: E2Z02 accrued 3123 patients from 3/06 to 5/08 at academic (n=6) and community (n=32) medical oncology clinics (see demographics table); 50% of E2Z02 patients had BrCa. Patients with nonmetastatic BrCa (OR 2.16, 95% CI 1.53-3.05), off therapy (OR 1.79, 95% CI 1.31-2.44), and white race (OR 1.64, 95% CI 1.10-2.46) had a higher chance of remaining employed than their counterparts. Patients with PS 0 were more likely to remain employed compared to patients with PS 1 (OR 1.85 95%CI 1.36-2.5) or PS 2-4 (OR 2.61, 95% CI 1.25-5.44). Age and TNs were not significant. As to the level of employment, nonmetastatic patients (OR=1.60, 95% CI = 1.17-2.21) and patients with better PS (P<0.0001) worked more hours in the workforce than their counterparts. Conclusions: This analysis identifies additional risk factors for employment changes in BrCa patients. Further research is needed to understand the complex relationship between race, other predictors and employment status. These findings could define a group of BrCa survivors at risk for changes in employment outcomes, and potentially allow for targeted interventions.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-07.
Abstract P2-14-08: Patient Perspectives on Information Communicated Regarding Effects of Treatment on Fertility
Authors: Goldfarb SB , Kelvin JF , Thom B , Kaplan J , Corcoran S , Margolies A , McCabe MS , Norton L , Hudis C , Basch E , Dickler MN.
Published: April 2011

Background: Many breast cancer survivors diagnosed during their reproductive years desire to have children after treatment and are distressed about the possibility of treatment-induced infertility. Informing patients about fertility preservation options before therapy may optimize quality of life after treatment. This study was undertaken to evaluate the information patients received about effects of therapy on fertility, early menopause, and fertility preservation options. Methods:

An IRB approved cross-sectional study was performed to evaluate patient perceptions of the impact of treatment on fertility and early menopause. The survey was developed at Memorial Sloan-Kettering Cancer Center (MSKCC) for patients ages 18-45, with items derived from existing surveys in the literature and input from a multidisciplinary committee. We evaluated two groups of patients, one who had completed treatment and the other who was currently undergoing therapy. Surveys were mailed to 395 women who began treatment (all modalities) for breast cancer at MSKCC between 7/1/07 and 6/30/08. A second cohort of patients (n=35) completed surveys during patient visits to breast cancer medicine ambulatory clinics

between 3/22/2010 and 4/8/2010.

Results:

The survey was completed by 159 pts. (129/395 and 30/35). At the time of diagnosis, 69% (110/159) had children and 45% (70/156) were interested in having children. 79% (123/155) reported that the impact of treatment on fertility was discussed with them before initiating therapy. A healthcare provider initiated the discussion 54% (83/155) of the time. However, only 35% (54/152) and 47% (71/150) of women felt they received an adequate amount of information about the effect of cancer treatment on fertility and menopause, respectively. Based on their ranking, patients preferred to receive fertility information in person either from their physician or a fertility specialist, or through written material. After treatment, 5 patients attempted pregnancy (7 naturally, 1 with assisted technology), yielding 8 live births. Conclusions:

Many breast cancer survivors wish to have children after treatment. To optimize success, patients should be adequately informed about the effects of therapy on fertility, early menopause, and options for fertility preservation. These findings are informing an institution-wide fertility program.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-08.
Abstract P2-14-10: Self Reported Cognitive Function in Breast Cancer Survivors: A 12 Month Longitudinal Descriptive Study
Authors: Barton D , Burger K , Novotny P , Sloan J.
Published: April 2011

Background: Changes in cognitive function are commonly reported in breast cancer (BC) survivors. Longitudinal studies have only recently been completed and are few. In particular, long term studies are lacking. The purpose of this abstract is to describe self-reported cognitive changes in women before the start, or after the first cycle of chemotherapy, through 12 months.

Methods: The data for this analysis were collected as part of a placebo-controlled randomized trial evaluating ginkgo biloba for the prevention of cognitive decline during adjuvant chemotherapy for BC. As there was no evidence that gingko biloba impacted cognitive function in any way, the sample was combined. Descriptive statistics were calculated to obtain the percent of women reporting worse perceived functioning or changes in their cognitive function at the start of chemotherapy, at the completion of treatment, and at 6, 12 and 24 months later (24 month data still being analyzed). 210 women, mostly white and mostly beginning anthracycline based chemotherapy, completed self report measures of cognition throughout the study. Women rated 10 areas of functioning by choosing a number from 1, signifying “functioning extremely less than normal”, to 7, signifying “extremely better than normal”. A score of 4 represented functioning perceived as “normal” for the respondent. Results: At baseline and after chemotherapy, the means for all 10 self reported cognitive items indicated “less than normal” functioning. Areas with the worst functioning included memory, ability to think clearly, staying focused, and planning ahead. At 6 and 12 months after chemotherapy, a percentage of participants reported worse functioning compared to baseline in every area. Changes in functioning are in the table below.

Table 1

At 12 months, the mean for only 4 items indicated these areas were at “normal” functioning. These were the ability to learn, solve problems, react quickly and balance a checkbook.

Discussion: For a subgroup of women, cognitive changes continue to worsen throughout 12 months and for many, perceived deficits remain.

Areas most negatively impacted relate to attention, memory and executive function. Future research should focus on identifying predictors of worse functioning and continued research is needed to elucidate targets for intervention research to prevent unwanted cognitive changes.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-10.
Abstract P2-14-12: Contents Preferred for a Post Treatment Survivorship Care Plan for Breast Cancer Survivors
Authors: Singh-Carlson S , Gotz C
Published: April 2011

Background: Current evidence indicates that the range of survivorship issues that patients can encounter is broad and can include physical, psychological, social and spiritual aspects. Studies also show that breast cancer survivors (BCS) may feel isolated and uninformed after completion of active treatment, when they have less interaction with health professionals. Although, Institute of Medicine's report on cancer survivorship recommends that cancer patients completing treatment should be provided with a comprehensive care summary and follow up plan that is clearly and effectively explained, it is not always practiced in oncology care.

Methods: A qualitative approach was used to explore impacts of breast cancer on survivors at different life stages and to determine preferred content and format of survivorship care plan (SCP). Focus group and face-face interviews were audio-recorded and transcribed with women who had non-metastatic breast cancer, 3-48 months post-treatment and were 18-75 years of age. Groups were stratified by age into <44, 45-54, 55-64, and >65. Transcripts were subjected to thematic and content analysis by age group (life stage).

Results: Results from16 women interviewed from the 4 age groups show that the impacts of breast cancer were broad and varied by age group. Physical, emotional and social effects were more intense in younger patients with women in the middle age group experiencing more concerns centered on financial and social support issues. Fatigue, fear of the unknown, and fear of recurrence were the most universal effects. Although customized SCP was preferred, important elements include: treatment summary, information on nutrition/exercise, expected side effects, signs/symptoms of recurrence, follow-up schedule, and updates on changes to recommended care. Preferred format for SCP is similar for all groups. Women preferred oncology nurses to provide the SCP at the beginning or at the end of the treatment and preferred written materials in lay language, telephone follow-up resource person and electronic bulletins for communicating updates.

Discussions: BCS are diversely impacted by the breast cancer experience. Effects vary by life stage, which impacts preferred content of SCP, but not format. Qualitative information on the impact of breast cancer at different life stages can be used to help customize content of SCPs.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-12.
Abstract P2-16-04: Plasma Biomarker Analyses in the AVADO Phase III Randomized Study of First-Line Bevacizumab + Docetaxel in Patients with Human Epidermal Growth Factor Receptor (HER) 2-Negative Metastatic Breast Cancer
Authors: Miles DW , de Haas SL , Dirix L , Chan A , Pivot X , Tomczak P , Provencher L , Delmar P , Scherer S.
Published: April 2011

Background: Inhibition of vascular endothelial growth factor (VEGF) signaling by bevacizumab (Bv; Avastin) combined with chemotherapy (chemo) is associated with improved clinical benefit in several malignancies, including metastatic breast cancer (mBC). Bv+chemo was evaluated in HER2 negative mBC in AVADO where baseline biomarker (BM) sampling was included as an optional element to identify prognostic and predictive biomarkers. Different angiogenic markers have been evaluated in trials containing Bv, with most trials having focused on circulating VEGF. Thus far, VEGF seems to have more a prognostic than predictive value as demonstrated across different indications (lung, renal, and colorectal cancer [Bernaards et al. ASCO 2010]). Trends for the predictive value of intracellular adhesion molecule-1 (ICAM-1) have been noted in two NSCLC studies (E4599 and AVAiL) and for basic fibroblast growth factor in AVAiL. The value of angiogenic plasma markers has not yet been established in mBC.

Material and Methods: In AVADO, 736 mBC patients (pts) were randomized to docetaxel 100mg/m2 plus either Bv7.5mg/kg, Bv15mg/kg or placebo. Primary endpoint was progression-free survival (PFS). Baseline plasma samples were analyzed for VEGF, ICAM-1, VEGF Receptor 1 and 2 (VEGFR1, 2), E-selectin and vascular cell adhesion molecule-1 using a novel ELISA based multiplex assay. Samples for BM analysis were available for 396 pts, equally distributed across treatment arms. Median levels of these markers were pre-specified as a cut point to categorize pts as low or high. Pre-treatment values were correlated with PFS (before start of subsequent antineoplastic therapy) using simple and multiple regression approaches as well as subgroup analyses.

Results: All subgroups had HR point estimates in favor of the Bv arms, with the exception of pts with low VEGFR2 levels at a Bv dose of 7.5mg/kg. In general, high plasma levels of VEGF and VEGFR2 were associated with better treatment effect in this study. Low ICAM-1 levels did not show the trend towards a larger treatment effect previously seen in E4599 and AVAiL. Further analyses will be presented.

Discussion: We report the first plasma BM data in a phase III placebo-controlled randomized study in mBC with Bv. In this subset analysis, using a novel ELISA assay, VEGF and VEGFR2 were identified as promising candidates for predictive value for PFS. A similar observation has been made in an independent BM analysis of pancreatic cancer (AVITA; data on file). Plasma data have so far not shown these trends in mCRC and mNSCLC. Further prospective evaluation of these markers is warranted. Authors D.W.M. and S.L.d.H. contributed equally.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-04.
Abstract P2-16-12: First-Line Bevacizumab Combined with Paclitaxel in Triple-Negative Locally Recurrent/Metastatic Breast Cancer: Subpopulation Analysis of 115 Patients Treated in Routine Oncology Practice in Germany
Authors: Schneeweiss A , Foerster FG , Hollburg W , Tesch H , Klare P , Wuelfing P , Distelrath A , Schumacher C , Steffens C-C , Schubert R , Widing A , Kasper C , Schmidt M.
Published: April 2011

Background: Both progression-free survival (PFS) and response rate (RR) are significantly improved when bevacizumab (Bev) is combined with first-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC), as demonstrated in three randomized, phase III trials (E2100, AVADO, RIBBON-1). The benefit derived from Bev appears to be similar in triple-negative (TN) and non-TN LR/mBC according to subanalyses of the randomized trials. We conducted a subpopulation analysis of TN patients treated with first-line Bev-paclitaxel (Pac) in a large German observational study in the context of routine oncology practice. Methods: Patients with HER2-negative LR/mBC received first-line Bev-Pac according to the European label at the time of study design. Safety and efficacy data were collected for up to 1 year (or until progression, death, or Bev discontinuation if earlier). The endpoints were safety and efficacy (PFS and RR). We conducted an exploratory analysis of the subset of patients with TN disease.

Results: Of the 567 patients for whom data are currently available, 115 (20%) had TN disease. Baseline characteristics and efficacy are summarized below. Overall survival data are immature and follow-up is continuing.

Conclusions: In this ongoing study, first-line Bev-Pac demonstrated a 51% RR and median PFS of 7.7 months in patients with TN LR/mBC. These data are consistent with findings from retrospective analyses of randomized phase III trials and a subpopulation analysis of the ATHENA study. Prospective trials evaluating Bev combination regimens in TN breast cancer are ongoing.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-12.
Abstract P2-16-13: Phase II Open Label Trial Bevacizumab in Combination with Paclitaxel and Gemcitabine as First Line in Patients with HER-2 Negative Recurrent or Metastatic Breast Cancer (AVALUZ): First Analysis
Authors: Salvador J , Jaen A , Ciruelos E , Codes de Villena M , Gil M , Murias A , Galan A , de la Haba J , Jara C , Bayo J , Baena JM , Casal J , Mel JR , Blancas I , Gonzalez E , Perez D , Manso L.
Published: April 2011

Background:

The combination of bevacizumab with taxanes, capecitabine or anthracyclines has shown increased progression-free survival in patients with metastatic breast carcinoma. The aim of this study is to evaluate the efficacy and toxicity profile of the combination of bevacizumab with gemcitabine and paclitaxel, providing a preliminary analysis of response in patients included for whom at least one response assessment and the toxicity experienced in all patients treated.

Methods:

A Phase II multicenter, national, open-label study in patients diagnosed of recurrent or metastatic HER-2 negative breast carcinoma, treated with first-line bevacizumab 10 mg/kg, paclitaxel 150 mg/m2 and gemcitabine 2000 mg/m2 day 1 and 15 c/28d until disease progression, unacceptable toxicity, or medical decision. This abstract evaluates efficacy by the response rate and the toxicity profile of the combination in all cycles of all patients included. The primary end-point of the study is PFS. Toxicity is evaluated according to NCI CTC v 3.0 criteria. Results:

From January 2009 to December 2009, 82 evaluable patients were recruited in 23 sites, with at least one response assessment available in 69. Median age 51.5 (26-81), ER+ 59 pts, PR+ 51 pts, triple negative patients 16 and previous chemotherapy (neoadj or adj) 58 pts. Of the 69 pts with response assessment, the last assessment is in cycle 3 for 31.88% of patients, cycle 6: 33.33%, cycle 9: 4.35%, cycle 12: 1.45% and at the end of treatment 29%. The median cycles administered per patient is 6 (1-14) and the relative median dose intensity is 0.93 for bevacizumab, 0.91 for paclitaxel, and 0.93 for gemcitabine.

The overall response obtained was 69.57%, with a clinical benefit of 89.86% (CR 8.7% (6), PR 60.87% (42), SD 20.29%, and DP 10.14%). Of the 82 patients with a median follow-up of 7.19 m (0.16-13.98), grade 3-4 toxicity affected 41%, with treatment discontinuation for adverse events in 19.51%. Eighteen SAEs were reported: pyrexia (4), infection at catheter site (2), urine infection and a single case of angor, hypertension, pulmonary embolism, pleural effusion, febrile neutropenia, neutropenia, vomiting, diarrhoea, dehydration, atrial fibrillation, and dizziness. Toxicity was generally easily controlled. Conclusions:

Although data from the primary study endpoint (PFS) are not yet available, the treatment regimen obtained a high overall response in patients treated and was well tolerated by this patient group.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-13.
Abstract P2-20-01: Safety and Clinical Efficacy of Multiple Booster Inoculations with the E75 Adjuvant Breast Cancer Vaccine
Authors: Vreeland TJ , Clifton GT , Patil R , Clive KS , Sears AK , Holmes JP , Mittendorf EA , Ponniah S , Peoples GE.
Published: April 2011

Background: We are conducting clinical trials of the HER2/neu E75-peptide+GM-CSF vaccine in clinically disease-free breast cancer patients at high risk for recurrence. Our Phase I/II trials have shown that the vaccine is safe and effective in stimulating clonal expansion of E75-specific CD8+ T-cells; however, this peptide-specific immunity decreases over time. Due to this waning immunity, a voluntary booster program was initiated. Methods: Node-positive and high-risk node-negative patients who were clinically disease-free after surgery and standard adjuvant therapy were enrolled. HLA-A2/A3+ patients were vaccinated (VG), while HLA-A2/A3-patients were followed as controls (CG). Patients who were ≥6 months from the completion of their primary vaccination series (PVS) were offered booster inoculations every 6 months. Patients were monitored for local and systemic toxicity. Orthagonal mean of local reactions (LR) were measured after each booster inoculation. In HLA-A2+ patients, E75-specific CD8+ T-cells were quantified using the HLA-A2:IgG dimer immediately before and 1 month after each booster administration. Patients were monitored clinically and radiographically for recurrences.

Results: 188 patients were enrolled (109 VG, 79 CG). Fifty-three of the VG patients received at least one booster (B1), with 33 receiving a second booster (B2), and 20 a third booster (B3). Booster inoculations were well-tolerated with only grade 1 and 2 local and systemic toxicities. Compared to the LR at the end of the PVS (mean = 82±3mm), the mean LR increased at B1 (88±3 mm, p=0.13), B2 (94±6, p=0.02), and B3 (93±10 mm, p=0.04). Average CD8+ E75-specific T-cells did not change significantly prebooster (1.1±0.1%) compared to post-B1 (1.1± 0.1%, p=0.71) or post-B2 (1.4±0.2%, p=0.27) but did increase significantly post-B3 (2.4±0.3%, P<0.01). Additionally, the percentage of HLA-A2+ patients with significant residual immunity (defined as >0.5% CD8+E75-specific T cells) increased from pre-booster (29/43, 67%) to post-B3 (16/16, 100%; p=0.01). With 24 month clinical follow-up complete in all enrolled patients, there has been a nonsignificant decrease in recurrences observed in the VG compared to the CG (6.5% vs 13.1%, p=0.19), with no recurrences in patients who had received at least one booster inoculation by 24 months (0/40, 0%, vs 13.1% in CG, p=0.03).

Conclusions: The HER2/neu E75 peptide vaccine stimulates immunity that is maintained or increased with booster inoculations in disease-free breast cancer patients. The booster inoculations are safe, with minimal toxicity. The clinical efficacy of the E75 vaccine with booster inoculations will be further evaluated in a phase III trial.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-20-01.
Abstract P3-01-03: The Predictive Value of Serum Serum Her-2/neu for Response to Anthracycline-Based and Trastuzumab-Based Neoadjuvant Chemotherapy of Advanced Primary Breast Cancer
Authors: Jeon C , Lee JS , Min W
Published: April 2011

Background:There excists little information about a possible influence of serum Her-2/neu on response to chemotherapy. We aimed that the assessment of serum Her-2/neu in pretreatment serum sample can be useful in predicting response to neoadjuvant chemotherapy. Methods: All breast cancers were tested by immunohistochemical stain and FISH for Her-2/neu before treatment. Serum Her-2/neu was twice measured by Chemiluminescence immunoassay (ADVIA centaur®TMsystem) before neoadjuvant chemotherapy and before operation. The cutoff value was 10.2 mg/ml according to previous study. Pathologic complete response (pCR) was considered as no residual tumor or remnant ductal carcinoma in situ, partial response (PR) was less than 50% decrease in maximal diameter in pathologic tumor size.The measurements for the change of serum Her-2/neu were defined as pretreatment Her-2/neu — preoperation Her-2/neu. We compared the change of serum Her-2/neu between 1) before prechemotherapy and after chemotherapy 2) pathologic complete response and partial response 3) trastuzumab (H) group and anthracyline (A) group. Results: Serum Her-2/neu was decreased after neoadjuvant chemotherapy. Mean of serum Her-2/neu in prechemotherapy was 15.4±9.0 ng/mL, that of postchemotherapy was 10.5± 2.0 ng/mL (p= 0.04). Pathologic response was correlated with the change of serum Her-2/neu (PR: 6.1 ng/ml vs. pCR: 42.0 ng/ml, p= 0.014). Serum Her-2/neu of trastuzumab group was more decreased than of anthracyline group (H=12.9 ± 14.5 ng/mL ; A= 2.2 ± 1.2 ng/mL; p=0.024). In trastuzumab group, pCR was boreline significantly correlated with change of serum Her-2/neu (PR: 0.8 ± 0.84 ng/ml vs. pCR: 21.1 ± 13.2 ng/ml, p= 0.08). Conclusions: Prechemotherapy serum Her-2/neu was to be a significant predictor of pathologic response to neoadjuvant chemotherapy. Serum Her-2/neu levels during treatment were associated with pathologic response in patients receiving neoadjuvant chemotherapy, particularly, in trastuzumab-based regimen. Serum Her-2/neu levels may serve to monitoring neoadjuvant therapy in Her-2/neu overexpressed breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-01-03.