Citations

Abstract CYR61 render human breast cancer cells highly resistance to the microtubule-interfering agent Taxol, a drug of choice for the treatment of metastatic breast cancer. The angiogenic factor CYR61 and its receptor avβ3 are markedly up-regulated in very aggressive breast carcinomas. Integrin signaling has been shown to modulate cancer cell responses to chemotherapy agents. Thus, the signal transduction pathways initiated by integrin may be a potential target for inhibiting cell survival during cytotoxic drug exposure. However, the molecular mechanism for CYR61-induces cytoprotection still unknown. Our data demonstrates that functional blockade of avβ3 with a synthetic chemical peptidomimetic based upon the αvβ3 the RGD (Arg-Gly-Asp) motif, is specifically cytotoxic towards CYR61-overexpressing breast cancer cells and that pharmacological interference of the CYR61/αvβ3 interaction restores Taxol efficacy. This data suggests that a previously unrecognized CYR61/αvβ3-driven cellular signaling actively modulates cell growth, apoptosis and chemosensitivity. To better understand the mechanism by which CYR61 induces Taxol resistance, we studied a series of molecular events and reveal that CYR61 prevents Taxol induction of p53 accumulation, blocks p21WAF1/CIP1 overexpression, and furthermore we demonstrated that CYR61 induces JNK activation. These observations suggest that increased expression of CYR61 could promote a chemoresistance by suppressing a specific pro-apoptotic signaling while still given chemotherapeutic treatments to induce cell damage. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1139.

Abstract Experiences at time of breast cancer (BC) diagnosis are associated with patient psychological health several months to years later; however, little investigation of this relationship during initial period following diagnosis has been undertaken.METHODS:This prospective study was designed to characterize the experience of receiving cancer diagnosis in women initiating treatment for BC (Stage 0 to III) and to identify associations between this experience and early psychological adjustment, hopefulness, and satisfaction with medical care. 121 women who recently received BC diagnosis prompting referral to specialty center responded to questionnaires assessing their experiences and coping styles:1. Experience Receiving Breast Cancer Diagnosis (ERBCD), categorizing patient demographic, medical, and psychosocial factors; context factors (location, privacy); clinician factors and behaviors.2. Cancer Diagnostic Interview Scale (CDIS) for perceived psychotherapeutic techniques used by clinican conveying cancer diagnosis.3. Mental Adjustment to Cancer Scale (MAC) for coping styles of fighting spirit, hopelessness/helplessness, anxious preoccupation, fatalism, and avoidance.Subjects completed the Profile of Mood States (POMS), Spielberger State-Trait Anxiety Inventory (STAI) and ratings of hopefulness and satisfaction. Multivariate regression analysis was employed with scores from POMS, STAI, hopefulness and satisfaction as dependent variables and values from ERBCD, CDIS and MAC as independent variables.RESULTS:Patients received diagnosis from general physicians, surgeons, radiologists, nurses, NP/PAs, gynecologists, breast specialists, family members, and secretaries. BC diagnosis was disclosed by telephone (59%), face-to-face (40%), letter (1%) and spouse (1%). Mean CDIS-Caring score was 3.4 ± 1.1 and CDIS-Competence was 4.0 ± 0.9 of 5.0. Results of multivariate regression analysis are shown:POMS-Total Mood DisturbanceIndependent VariableParameterSEP ValueAge-0.6600.2760.0183MAC-Fighting Spirit-1.1550.4360.0093MAC-Anxious Preoccupation5.2720.780< 0.001 STAI-State AnxietyIndependent VariableParameterSEP ValueRecent Stress Level0.9420.3710.0127MAC-Fighting Spirit-0.3670.1480.0147MAC-Anxious Preoccupation1.9740.271<0.0001MAC-Avoidant4.4671.4950.0036 Satisfaction was predicted by CDIS-Caring, individual conveying diagnosis, type of information helpful, feeling concerns were understood.CONCLUSIONS:Experiences receiving BC diagnosis are variable and associated with hopefulness and satisfaction. Age, recent stress level and predominant coping style appear more predictive of psychological adjustment (POMS, STAI) than experience receiving BC diagnosis. Understanding these relationships provides direction for future research and clinical interventions to identify patients at risk for early mood disturbance and anxiety following BC diagnosis and to modify aspects of conveying BC diagnosis that influence hopefulness and satisfaction with medical care.HopefulnessIndependent VariableParameterSEP ValueCDIS-Caring0.4270.088<0.0001Diagnosis by Telephone0.3810.1770.0338Opportunity to Ask Questions0.4440.2270.0535Recent Stress Level-0.0820.0290.0057MAC-Fighting Spirit0.0430.0120.0005MAC-Anxious Preoccupation-0.0610.0230.0098 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1069.

Abstract Abstract #MS1-1 In this mini-symposium, we will address the major risk factors for breast cancer, current risk prediction tools, and measures to reduce risk in those women deemed at high risk. Those factors that convey a significantly increased risk of breast cancer (e.g. relative risk greater than 4.0) include: strong family history of breast cancer (i.e. early onset of disease, multiple relatives with disease, including BRCA1/2 carriers); atypical hyperplasia on benign biopsy; older age; and dense breast tissue. Multiple other features are recognized as contributing to breast cancer risk but to a lesser degree. These include having a family history of breast cancer but not with a hereditary pattern (RR approximately 2.0), benign breast disease (RR 1.5), multiple reproductive factors including early menarche, late menopause, current or recent estrogen plus progesterone use, current OC use (all with relative risks in the 1.2-1.3 range); and alcohol use (e.g. 3 drinks per day) (RR∼1.3). Numerous other features such as induced abortion and sedentary lifestyle have been reported to increase risk of breast cancer but to a very minor degree and results are not consistent.
 Several risk prediction models for breast cancer focus on an individual's likelihood of carrying a hereditary predisposition to the disease (e.g. Frank, Couch, Shattuck-Eidens, Parmigiani, BRCAPRO, BOADICEA, Claus). Outside of the hereditary setting, the most widely used tool is the Gail model. Features incorporated in the Gail model include age, family history, number of breast biopsies, age at menarche, age at first live birth, and the presence of atypia on a benign biopsy. While the Gail model has been shown to be calibrated in predicting number of breast cancers likely to develop in groups of women, its discriminatory accuracy in predicting risk for individual women is limited. This limitation is not well appreciated by many clinicians.
 Regarding options for surgical risk reduction in high risk individuals, several studies examined the efficacy of both bilateral and contralateral mastectomy in women at increased risk for breast cancer, including BRCA1/2 carriers. Results consistently show a greater than 90% reduction in risk of subsequent breast cancer. A study by the Cancer Research Network (6 HMOs) examined the impact of contralateral PM on mortality from breast cancer and showed reduced death from breast cancer with CPM (HR 0.57 [0.45-0.72]).
 Studies of risk-reducing salpingo-oophorectomy (RRSO) in BRCA carriers have shown dramatic reductions in risk of subsequent ovarian/peritoneal cancer, providing approximately 90% protection. The reduction in breast cancer risk after RRSO is seen only when the oophorectomy is performed in premenopausal women. Recent data on 368 BRCA1 and 229 BRCA2 carriers from a multicenter study show a differential effect on breast cancer risk following RRSO by mutation type. The hazard ratio for risk of breast cancer in BRCA2 carriers was 0.28 (0.08-0.92) (p 0.04) but for BRCA1 carriers was 0.61 (0.30-1.22) (p 0.16). This appeared to be due to the preponderance of ER-negative breast cancers in BRCA1 carriers, where no risk reduction with RRSO was seen. (N Kauff et al, JCO, 3/10/08) Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr MS1-1.

Abstract Abstract #76 Background: QOL and MH outcomes were integrated into the NSABP B-30 trial as secondary outcomes to the efficacy analyses which are being presented separately. Explicit secondary aims of the NSABP B-30 study were 1) to compare toxicities among the regimens, 2) to compare QOL, and 3) to examine differences in amenorrhea and its relationship to symptoms, QOL, and efficacy. Here we examine the secondary aims of the study as a companion to the efficacy results that are presented separately.
 Materials and Methods: 5351 pts with cT1-3, N0-1, M0 were enrolled from 3/1/99 to 3/31/2004. 2170 were enrolled on the QOL study, and 2449 were enrolled on the MH study and were randomized to one of three treatment groups: Group 1 [doxorubicin (A) 60 mg/m2 and C 600 mg/m2 q 3 weeks (wks) x 4 followed by docetaxel (T) 100 mg/m2 q 3 wks x 4; Group 2 [A 50 mg/m2 and T 75 mg/m2 q 3 wks x 4]; Group 3 [A 50 mg/m2 T 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 q 3 wks x 4]. All patients with ER-positive tumors received hormonal therapy after completing chemotherapy. Preliminary results from Group 1 have been reported previously (Swain, et al. Breast Cancer Res Treat, 2008).
 Results: The protocol specifies that 800 deaths are required for the definitive analysis of treatment, QOL, and MH outcomes, which are expected to occur by fall 2008. For this final report, results from a comparison of the three arms will be analyzed and presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 76.

Abstract Abstract #75 Background: The primary aims of this study were to determine 1) if a concurrent regimen of therapy containing cyclophosphamide compared to a sequential regimen containing cyclophosphamide would prolong disease-free survival (DFS) and overall survival (OS) and 2) if a regimen without cyclophosphamide was at least as efficacious as the two regimens containing cyclophosphamide. The secondary aims were to compare toxicities among the three regimens and to compare differences in amenorrhea in premenopausal women in each arm and its relationship to outcome.
 Materials and Methods: 5351 pts with cT1-3, N0-1, M0 were enrolled from 3/1/99 to 3/31/2004. 1783 pts were randomized to Group 1 [doxorubicin (A) 60 mg/m2 and C 600 mg/m2 q 3 weeks (wks) x 4 followed by docetaxel (T) 100 mg/m2 q 3 wks x 4], 1784 pts to Group 2 [A 50 mg/m2 and T 75 mg/m2 q 3 wks x 4], and 1784 to Group 3 [A 50 mg/m2 T 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 q 3 wks x 4]. All patients with ER-positive tumors received hormonal therapy after completing chemotherapy. The protocol specifies that 800 deaths are required for the definitive analysis. This is expected to occur by Fall 2008.
 Results: Mean time on study is currently 79 months. At entry, 46% of pts were < 49 yrs; 54% were > 50 yrs. 82% were white, 10% black, 4% Hispanic. 66% had 1-3 positive nodes, 26% had 4-9, and 8% had 10+. 75% of pts were ER pos. 49% had lumpectomy, 51% mastectomy, and 24% local/regional radiotherapy. Mean tumor size was 2.5 cm. The presentation will include the first results of DFS, OS, and relevant toxicities from the trial. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 75.

Abstract Abstract #62 Background: Breast cancer is the leading cause of cancer deaths in younger women (25 to 49 years of age). Young women with breast cancer also have worse overall survival and increased risk of recurrence compared to older women with breast cancer. Innovative approaches to understanding risk factors and tissue characteristics for the younger population can improve understanding of breast cancer etiology and enhance risk-stratification for these women. This study was aimed at examining breast cancer risk factors among young women (<50 years) with BBD. Materials and Methods: Utilizing the Mayo Clinic Surgical and Pathology Indices, women ages 18 to 85 who had benign excisional breast biopsy between January 1, 1967 and December 31, 1991 were identified. The diagnosis of breast cancer served as the study endpoint and was determined using the Mayo medical record and questionnaire information from study participants. The breast pathologist, blinded to the initial diagnosis and clinical outcome, performed pathology review. BBD was classified as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). Age-related lobular involution (reduction in number and size of acini per lobule) was classified as none-0%, partial- 1 to74%, or complete- >75% involution. Relative risk (RR) was estimated by comparing the number of observed breast cancers with the number expected, based on breast cancer rates in the Iowa Surveillance, Epidemiology, and End Results registry. Results: Of the 9376 women in the Mayo BBD cohort, 4460 women were aged <50 years at BBD diagnosis and formed the study cohort. The mean age at BBD diagnosis was 39.4 (+ 8.3) years. With a median follow-up of 20 years, 326 breast cancer cases were identified. The histologic findings were NPD in 72% of women, PDWA in 26%, and AH in 2%. The relative risk of breast cancer for the overall cohort of young women with BBD was 1.5 (95% CI [1.4, 1.7]). The relative risk among those with AH was 6.9 (95% CI [4.6, 10.1), compared with a RR of 2.0 (95% CI [1.7, 2.4]) for PDWA, and RR of 1.2 (95% CI [1.0, 1.4]) for NPD. Risk was associated with extent of lobular involution (RR for no involution was 1.7 (95%CI [1.4, 2.1]); partial involution 1.4 (95%CI [1.2, 1.7]); complete involution 0.7 (95%CI [0.3, 1.4]). Family history was available for 83% of the cohort and RR was 2.2 (95% CI [1.7, 2.8]) for women with strong family history and was 1.3 (95% CI [1.1, 1.6]) for women with no family history. Discussion: Young women with BBD are at increased risk of breast cancer. Risk is high in women with atypical hyperplasia, and those with a family history of breast cancer. Lobular involution is associated with reduced breast cancer risk in this population, suggesting a role in modifying breast cancer risk. These findings suggest the need for further research in this population, along with tissue-based studies to examine the processes leading to breast cancer, and enable identification of those women at highest risk. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 62.

Abstract Abstract #6149 Background: Internal Review Boards and Data and Safety Monitoring Boards often require protocol-specified adverse event (AE) stopping rules for safety monitoring. However, availability of safety data for investigational agent(s) may be limited at the time of protocol development in the phase II setting. This meta-analysis was undertaken to quantify the variability of AE rates in North Central Cancer Treatment Group (NCCTG) phase II metastatic breast cancer (MBC) clinical trials and to investigate whether study factors are associated with AE rates for the development of AE stopping rules in future phase II clinical trials.
 Methods: All closed NCCTG phase II MBC clinical trials using CTC v2.0 or CTCAE v3.0 for AE monitoring were selected. Rates of G3/4 AEs (overall, hematologic [H], and non-hematologic [NH]) and of study discontinuation [SD] due to AEs were calculated for each trial. Associations between study factors [number of agents (single vs combination); line of therapy (first-line only vs other); and type of therapy (chemotherapy vs other)] and AE rates were assessed via Wilcoxon rank sum tests.
 Results: 15 trials met inclusion criteria. 7 used CTCAE v3.0; 6 investigated single agents; 5 investigated first-line therapy; and 11 investigated chemotherapy regimens. 694 pts were evaluable for AE analysis. The G3/4 AE rate across trials was 68% (16-98%) overall, 45% (0-96%) H, and 51% (16-78%) NH. The overall rate of SD due to AEs was 13% (0-40%). The overall rate of G3/4 AEs was significantly lower in single agents vs combination regimens (30% vs 86%, p=0.004). This association held for H (2% vs 66%, p<0.0001) and NH (27% vs 57%, p=0.03) Aes. The rate of SD due to AEs was also significantly lower in single agents vs combination regimens (0.5% vs 15%, p=0.04). The rate of G3/4 AEs was significantly higher in first-line only trials vs other trials (overall: 90% vs 47%, p=0.04; H: 73% vs 5%, p=0.02; NH: 66% vs 41%, p=0.08). The rate of SD due to AEs was also significantly higher in first-line only trials (18% vs 4%, p=0.008). The only significant association with chemotherapy vs other therapy was G3/4 H AE rates (51% vs 2%, p=0.02).
 Discussion: High variability in G3/4 AE rates overall and in H and NH AEs was noted in these 15 trials. There is also high variability in the rates of SD due to AEs. The data suggest that clinical trials with single agent regimens have lower AE rates than combination regimens and, surprisingly, trials of first-line therapy only have higher AE rates than other trials. This may be due to more aggressive therapy being tested in the first-line setting. Although data from previous trials with the investigational agent(s) should be used for developing AE stopping rules when available, this study suggests that study factors such as number of agents and line of therapy can be useful when previous data are limited. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6149.

Abstract Abstract #6147 Background: Phase II metastatic breast cancer (MBC) clinical trials evaluating efficacy of cancer treatments are often designed using a binary primary endpoint (i.e., each evaluable patient [pt] is classified as a “success” or “failure”). In the era of novel agents in cancer research, endpoints such as 6-month progression-free survival [PFS6] for measuring efficacy of cytostatic agents are more commonly being used. This meta-analysis was undertaken to compare two binary classifications of PFS6 and to compare these binary endpoints with other efficacy endpoints in the phase II setting.
 Material and Methods: All closed North Central Cancer Treatment Group (NCCTG) phase II MBC clinical trials using Response Evaluation Criteria in Solid Tumors (RECIST) with at least 1 year of follow-up since last pt accrued were selected. All eligible pts initiating treatment were included. Two binary classifications of PFS6 were computed for each trial. Success for PFS6-1 is defined as on study treatment 6 months from registration without documentation of disease progression. Success for PFS6-2 does not require a pt to be on study treatment at 6 months. Also computed for each trial are Kaplan-Meier (KM) estimates of PFS6 (PFS6-KM) and 1-year overall survival (OS1-KM). Trial-level endpoints were summarized using descriptive statistics and compared using weighted (by trial sample sizes) Pearson correlations. Lastly, the concordance rate of PFS6-1 and PFS6-2 status with OS status at 1 year at the pt level was computed across all pts (pts censored for OS prior to one year were excluded [n=10]).
 Results: 11 trials met inclusion criteria. All trials required measurable disease and had a single arm. 485 evaluable pts were accrued (median 48 pts per trial [range 19-77]). Median PFS6-1 was 27% (range 10-44%) and median PFS6-2 was 34% (range 10-73%). The median trial-level difference between PFS6-1 and PFS6-2 was 5% (range 0-43%). The correlation between PFS6-1 and PFS6-2 was 0.81 (p<0.01). Among the endpoints, PFS6-2 and PFS6-KM had the highest correlation (>0.99, p<0.01) due to only 2 pts being censored for PFS prior to 6 months. Among the PFS endpoints, OS1-KM was most highly correlated with PFS6-1 (0.79, p<0.01) with the correlations with PFS6-2 and PFS6-KM not being statistically different from zero (both 0.59 with p>0.05). However, overall patient-level concordance between PFS6 status and OS status at 1 year was higher using PFS6-2 (68%) than PFS6-1 (59%).
 Discussion: Differences were observed between the two binary classifications of PFS6. PFS6 with (as compared to without) the requirement that a pt be on study treatment at 6 months appears to have higher correlation with OS at 1 year at the trial level but lower concordance with OS status at 1 year at the pt level. Selection of the historical control should take into consideration the definition of PFS6 being used. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6147.

Abstract Abstract #6140 Background:
 Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in combination with capecitabine (C) in 2 large clinical trials in metastatic breast cancer (MBC) pts whose tumors were resistant to (study 046, JCO, 2007) or pretreated with anthracycline (A) and taxanes (T) (study 048). In 048, ixa + C, compared to C alone, demonstrated significant increases in PFS (HR 0.79 [0.69-0.90]) and ORR (43% vs 29%). A trend toward increased OS was seen both in 048 (HR 0.90 [0.78-1.03]) and in 046 (HR 0.90 [0.77-1.05]), which did not reach statistical significance. Similar to taxanes, dose-limiting peripheral neuropathy (PN) is a side effect associated with ixa treatment. Here we present the incidence rates, management of ixa-induced PN from 3 registrational studies in pts with MBC and an analysis of resolution time. Also, data on potential risk factors for PN are presented.
 Methods:
 Incidence of PN is summarized from a 2000 pt program from 3 multi-center clinical trials. In this program, almost 1100 pts with MBC received ixa either as a monotherapy (40 mg/m2 IV over 3h Q3w, N=126) in a phase II study, or in combination with C (1000 mg/m2 PO BID x14d Q3w) in 2 large phase III studies (N = 369 and N = 595). PN was evaluated every 4 weeks after completion of treatment until toxicity was resolved. Resolution of PN was defined as the time from onset of worst grade to baseline or grade 1. A Cox regression analysis was also performed on a dataset of 945 pts with different tumor types across multiple studies, receiving ixa as a monotherapy or in combination with C, to identify the potential risk factors for grade 3/4 PN.
 Results:
 Incidence rates of grade 3/4 PN and resolution time observed in 1 phase III study (046) and the phase II (081) have been published before (081: JCO, 25; 3407). Here we present the data from the final confirmatory phase III study (048).
 
 PN was effectively managed with dose reduction. After dose reduction, symptoms improved or did not worsen in the majority of pts, and a median of 2-3 additional treatment cycles were delivered. Pts with diabetes were at a higher risk of grade 3/4 PN (HR: 1.67 [1.00-2.78], p-value = 0.049).
 Conclusions:
 Incidence of ixa-associated PN was similar to that observed in trials of other T based regiments. Ixa-induced PN has a predictable median time to resolution of 5-6 weeks over 3 large studies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6140.

Abstract Abstract #6114 Introduction:
 Symptomatic patients (pts) with performance status (KPS) 70-80 with locally advanced or metastatic breast cancer (MBC) have worse prognosis than pts with good performance status and are often excluded from clinical trials. Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in 2 large clinical trials in combination with capecitabine (C) in MBC pts with tumors resistant to (study 046; JCO; 2007) or pretreated with anthracycline (A) and taxane (T) (study 048). In 048, ixa + C, compared to C alone, showed significant increases in PFS (HR 0.79 [0.69-0.90] and ORR (43% vs 29%). A trend toward increased OS was seen in 048 (HR 0.90 [0.78-1.03]) and 046 (HR 0.90 [0.77-1.05]) which did not reach statistical significance. In 046 and 048 trials, a survival benefit was seen with ixa + C in a predefined analysis in a subset of symptomatic KPS 70-80 pts (HR: 0.75 [0.58-0.98], 0.76 [0.60-0.96], respectively). We present a predefined pooled analysis of clinical outcomes in symptomatic pts from both studies to better evaluate the treatment effect in this subset.
 Methods:
 1973 pts with MBC previously treated with an A and T were randomized in phase III trials 046 and 048 to receive ixa (40mg/m2 IV over 3h Q3w) + C (1000mg/m2 PO BID x14d Q3w) or C alone (1250mg/m2 PO BID x14d Q3w). 606 pts from the 2 studies were KPS 70-80. Study outcomes included ORR, PFS and OS.
 Results:
 ORR, PFS and OS favored ixa + C in this pt population.
 
 In asymptomatic pts (KPS 90-100), similar improvement was observed in PFS and ORR; no benefit in OS was seen. Incidence of key treatment related grade 3/4 AEs for ixa + C in this subset of pts was similar to the overall population.
 Conclusions:
 In the pooled analysis, ixa + C demonstrates a survival benefit (2.8 mo) for symptomatic pts (KPS 70-80) failing A and T, which was consistently seen in this pt population in the individual studies as well, indicating that symptomatic pts can benefit from management of their disease and achieve overall clinical benefit with ixa combination. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6114.