bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-06-03: Truncated ERBB2 Receptors: Diagnostic and Therapeutic Targets
Authors: Ward T , Iorns E , Singh S , Jegg A-M , Gallas M , Lippman M , Landgraf R , Pegram M.
Published: April 2011

Background:

Patients with ERBB2+ breast cancer have aggressive disease and poor prognoses. It is now apparent that many ERBB2+ tumors also express truncated ERBB2 receptors (t-ERBB2s), namely p110 and p95. Increased expression of t-ERBB2s by breast tumors correlates with increased nodal involvement, distant metastasis, and poor clinical outcome in patients. Because t-ERBB2s lack the epitope bound by trastuzumab, expression of high levels of these isoforms may designate patients who would be better treated with alternative anti-ERBB2 therapy such as lapatinib; unfortunately, there is currently no clinical method to distinguish full-length p185- versus t-ERBB2 in patient tumor samples. Materials and Methods:

Recombinant forms of p185-, p110- and p95-ERBB2 were constructed using standard cloning techniques and expressed in human mammary epithelial cells (HMLE) via retroviral vector. The expression and subcellular localization of constructs were confirmed by western blot analysis and confocal microscopy. The ability of p185- and t-ERBB2 constructs to transform HMLE cells was evaluated using soft agar assays, and the effects on migration and invasion of these cells were investigated by transwell assays. Finally, the in vivo tumor formation by p185- vs. t-ERBB2 expressing cells was evaluated in immunodeficient mice. Additionally, a novel proximity-based antibody-capture method method to discern full-length versus t-ERBB2 in patient tumor samples was assessed (COPIA). Block tumors and fine-needle aspirates from patient tumor samples were used for quantifying total and phosphorylated ERBB2 receptors.

Results and Discussion:

Recombinant p185- and t-ERBB2 constructs were stably expressed in HMLE cells, and were correctly targeted to the cell membrane, as shown by confocal immunofluorescence microscopy and immunoblot. Expression of p110 t-ERBB2 increased migration and invasion of HMLE cells compared to p185 ERBB2 (P<0.0001), while p110, p95m and p185 ERBB2s were equally effective at enhancing anchorage-independent growth. In vivo, expression of p110 t-ERBB2 but not other isoforms led to increased tumor formation in mice compared to controls (P<0.005). No apparent phenotypes were elicited by expression of intracellular t-ERBB2 isoforms. Using COPIA testing, t-ERBB2 isoforms were detected in strongly ERBB2- positive tumors (16 of 31 samples, 52%) and were phosphorylated in 10 of 31 (32%). As expected, t-ERBB2s were not detected in ERBB2-negative tumor samples.

Truncated ERBB2s, particularly p110, may be major pathogenic drivers in ERBB2+ cancers. These isoforms may accelerate disease progression by promoting invasion and metastasis, and likely mediate resistance to trastuzumab and other therapies. Thus, t-ERBB2s represent attractive novel targets for diagnosis and treatment of ERBB2+ breast cancers.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-03.
Abstract P5-06-06: The Safety and Tolerability of Panobinostat (LBH589) in Combination with Capecitabine +/− Lapatinib: A Phase I Study in HER2+ Breast Cancer
Authors: Peacock NW , Jones SF , Yardley DA , Bendell JC , Infante JR , Murphy PB , Burris HA.
Published: April 2011

Background: Panobinostat is a histone deacetylase (HDAC) inhibitor, for which in vitro studies have suggested activity in breast cancer lines. This phase I study was designed to assess the safety, tolerability, and efficacy of panobinostat in combination with lapatinib and capecitabine in 3 parts. Part 1, for which we have previously reported findings (Peacock et al, ASCO 2010), established the maximum tolerated dose (MTD) of panobinostat (30mg twice weekly) in combination with capecitabine (1000mg/m2 BID). Part 2, reported here, was designed to assess the QTc prolongation and overall toxicity of panobinostat in combination with lapatinib in patients with HER2+ breast cancer. Part 3 will assess the tolerability and efficacy of the triplet combination based on doses defined in Parts 1 and 2. Method: Patients aged ≥18 years with incurable, locally recurrent or metastatic HER2+ breast cancer were eligible. Additional eligibility criteria included: < 3 prior treatments in the metastatic setting; ECOG PS 0-1; measurable disease by RECIST; no impairment of cardiac function; no prior treatment with HDAC inhibitors; informed consent. Lapatinib doses of 1000mg daily were administered with panobinostat doses of 15mg and 20mg three times weekly, following 1 week of 2 doses of panobinostat alone to assess QTc prolongation. Cycles were repeated every 21 days until disease progression or toxicity warranted drug discontinuation. Patients were reevaluated for response every 2 cycles.

Results: 5 female patients with HER2+ metastatic breast cancer were accrued to Part 2, with a median age of 66 years (range: 64 — 67); 80% of patients were ECOG PS 0. To date, patients have received 17 cycles of treatment (median 4 cycles), and 2 patients have stable disease (progression1, unevaluable 1, and too early to assess 1), with one patient remaining on treatment. There have been no dose-limiting toxicities. One patient was hospitalized for grade 3 peripheral neuropathy (unrelated). No grade 2/3/4 toxicities have occurred in >1 patient; no QTc prolongation has been observed.

Conclusions: Our preliminary findings suggest that the combination of panobinostat and lapatinib is safe and tolerable. No QTc prolongation or cardiotoxicity has been observed. Part 3 will evaluate the triplet combination using the dosages established in Parts 1 and 2.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-06.
Abstract P5-06-08: Role of Androgen Receptor in Metastasis and Hormone Resistance of Estrogen Receptor Positive Breast Cancer
Authors: Ciupek A , Brusco L , Covington KR , Weigel NL , Lu Y , Mills G , Fuqua SAW.
Published: April 2011

Background: We have previously developed a novel model of estrogen receptor a (ERa)-positive breast cancer metastasis involving shRNA knockdown of Rho GDIa, an inhibitor of the GTP hydrolyzing enzymes of the Rho family.Also although it is known that androgen receptor (AR) is frequently expressed with ERa in breast tumors, and is generally accepted to be a favorable prognostic factor, its role in tumor progression and metastasis is unknown.

Materials and Methods: shRNA knock down was used to lower endogenous expression of Rho GDIa in ERa-positive MCF-7 cells. Metastasis of the knockdown cells was analyzed by injection into athymic mice followed by histological analysis of isolated tissues. Resistance to Tam was also analyzed in these cells by following tumor growth in injected mice treated with vehicle or Tam. To determine the involvement of specific pathways, western blot analysis was used to determine expression of components of the AR and ERa signaling pathways. Reverse phase protein arrays (RPPA) were also used to analyze global expression of phosphorylated proteins. Results: The MCF-7-Rho GDIa knockdown cells exhibited increased lung metastasis, and both primary and metastatic tumors were resistant to the inhibitory effects of Tam. AR protein was found to be overexpressed in the Rho GDIa knock down cells as well, as confirmed by both western blot and RPPA. AR RNA levels were not increased however, thus post-transcriptional modifications via the Rho pathway may be involved in its up-regulation. In addition, AR protein levels were modulated by estrogen treatment in the knockdown cells, suggesting a role for ER in its regulation.

Discussion: Given that AR was significantly overexpressed with the metastatic and resistant phenotype of these cells, its role in these processes is currently being explored with AR antagonists. AR may represent a clinical target for hormone therapy resistance and metastasis of ERa-positive breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-08.
Abstract P5-08-01: Oncology Clinicians’ Knowledge, Attitudes and Practices Regarding Fertility Preservation
Authors: Goldfarb SB , Dickler MN , McCabe MS , Thom B , Jia X , Margolies A , Norton L , Hudis C , Basch E , Kelvin JF.
Published: April 2011

Background:

Many breast cancer survivors of child-bearing age wish to become parents after therapy and are concerned about the possibility of treatment-induced infertility. Educating patients about the effects of therapy on fertility, early menopause, and fertility preservation options prior to treatment may optimize a survivor's quality of life after treatment. It is unclear whether oncologists feel qualified to discuss fertility issues with their patients, and if not, what barriers prevent such discussions.

Methods:

An IRB approved cross-sectional survey was developed at Memorial Sloan-Kettering Cancer Center (MSKCC) in order for clinicians to self-evaluate their knowledge, attitudes, and behaviors regarding fertility preservation. Survey items were derived from existing surveys in the literature and input from a multidisciplinary committee. The web-based survey was systematically administered to all MSKCC ambulatory clinicians. Repeated email reminders were sent to optimize responses.

Results:

76 breast cancer clinicians at MSKCC and our regional network sites completed the survey between 2/9/09 and 2/25/09. Among respondents, there was widespread agreement (97% (70/72)) that patients should be informed of fertility preservation options, but fewer respondents (51% (37/72)) consistently discussed effects of treatment on fertility with their patients. Only 47% of clinicians (35/74) reported access to information about effects of treatment on fertility. Many physicians cited lack of training in fertility preservation, time constraints, and lack of referral information as barriers to educating patients. No significant difference existed in practice or knowledge between physicians who were practicing for ≤ 5 years vs ≥ 5 years.

Conclusions:

Physicians report that lack of education, resources and insufficient time hinder fertility preservation discussions with patients. Physicians might benefit from educational efforts regarding the effects of treatment on fertility and new fertility preservation techniques in order to effectively counsel their patients. Time limitations may be overcome by developing educational resources and collaborating with other clinical staff (e.g., nurses) to provide this vital information to patients. These findings are informing an institution-wide educational fertility program.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-08-01.
Abstract P5-09-01: Improving Informed Consent: Evaluating the First Decision Aid in a Clinical Trial Setting (IBIS-II Breast Cancer Prevention Trial)
Authors: Juraskova I , Butow P , Smith B , Seccombe M , Coates A , Boyle F , McCarthy N , Reaby L , Forbes JF.
Published: April 2011

Background: Recruitment to clinical trials is generally suboptimal, with both patients/consumers and clinicians reporting difficulties with the consent process. Decision Aids (DAs) are designed to facilitate doctor-patient communication and participation in decision-making, and may improve the consent process by ensuring patients/consumers make decisions that are informed and acted upon. While participant information sheets (PIS) provide information about the specific clinical trial, DAs present evidence-based information about all available management options (not just the clinical trial), including risks and benefits of each option. They also present both written and graphical forms of the information to enhance understanding, and explicit value clarification exercises to facilitate value-sensitive decisions. In screening and treatment settings, DAs have been found to reduce decisional conflict, improve patient knowledge, create more realistic expectations, and promote active decision-making without increasing anxiety. This RCT aimed to evaluate the efficacy of a DA for women at increased risk of breast cancer who are considering participation in the IBIS-II Prevention trial.

Methods: Women eligible for IBIS-II, who had not decided about participation, were invited to take part in the DA study. Participants from 12 Australian and New Zealand IBIS-II centres were randomised to receive either the standard IBIS-II information and consent materials alone (Control group, n=89), or in combination with a DA booklet (DA group, n=89). Participants completed standardised and purpose-designedmeasures 1 week and 3 months after deciding whether or not to participate in IBIS-II.

Results: In the Prevention arm, the majority of women (84%) reported the DA made it easier to understand IBIS-II compared to reading the PIS alone, and 89% recommended providing both the DA and PIS to potential IBIS-II participants. No group differences were detected in levels of decisional conflict or knowledge of IBIS-II/clinical trials in general, due to floor and ceiling effects respectively. Similarly, no group differences were found in levels of decisional regret and satisfaction at 3-month follow-up. Discussion: This is the first study to assess the effectiveness of DAs in a clinical trial setting. The use of DAs has been strongly endorsed by participating women and clinicians. Challenges of evaluating DAs in a Prevention breast cancer trial setting will be discussed. An RCT of a DA for the DCIS arm of IBIS-II is currently underway. The DAs have the potential to enhance the process of informed consent and reduce dropout rates in clinical trials.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-09-01.
Abstract P5-09-02: How Long Have I Got? Estimating Post-Progression Survival after First Line Chemotherapy for Metastatic Breast Cancer Based on Data from Randomized Trials
Authors: Kiely BE , Lee CK , Tattersall MHN , Stockler MR.
Published: April 2011

Background: Two recent systematic reviews have reported that median post-progression survival (mPPS) was typically double the median progression free survival (mPFS) in contemporary randomized trials of first line chemotherapy for metastatic breast cancer (MBC). We sought to determine the ratio of PPS to PFS and the accuracy of using simple multiples of PFS to estimate PPS in an independent dataset. Methods: We analysed survival data from 323 women in a randomized trial of capecitabine versus CMF as first line chemotherapy for MBC, both for the trial overall (using the median Kaplan Meier estimates: mPFS and mPPS), and for each individual woman (using her own PFS and PPS). PPS was estimated for each woman by (i) doubling her PFS (as per the systematic reviews), and (ii) by multiplying her PFS by the median of the individual patient ratios of PPS:PFS for this trial. Estimates were deemed accurate if they were within 0.75 to 1.33 times the actual value. The primary population of 221 women excluded 27 censored for progression, 65 censored for death, 8 with PFS <2 weeks, and 2 with PFS = OS. The secondary population included all 323 patients. Distributions were summarized by their medians and percentiles reflecting the typical range (25th to 75th, IQR), worst case (90th) and best case (10th) scenarios. Results: The median age was 62, ECOG PS was 0-1 in 87%, 46% had liver metastases and 64% had hormone receptor positive disease. Kaplan Meier estimates of survival times in months for the primary population (secondary population) were mPFS 5.3 (6.3), mPPS 8.8 (11), and mOS 16 (21). The ratio of mPPS:mPFS for the trial overall was 1.7. Ratios of PPS:PFS for individual women were lower with medians of 1.5 (IQR 0.6 - 3.1) in the primary population and 1.3 (IQR 0.5 — 3.0) in the secondary population. Estimates of a woman's PPS as double her PFS were accurate in 17% of women. Estimates of a woman's PPS as 1.5 times her PFS were accurate in 20% of women. When each woman's PPS was estimated as 1.5 times her PFS, 10% of women survived for less than 0.18 times their estimate (<0.18 x 1.5PFS), 10% survived for longer than 4 times their estimate (>4 x 1.5PFS)and the middle 50% survived between 0.37 to 2.1 their estimate (0.37 x 1.5PFS to 2.1x 1.5PFS). Analysis of accuracy in the secondary population gave similar results.

Conclusion: The ratio of mPFS:mPPS in this randomized trial was similar to that seen in recent systematic reviews, but higher than the individual ratios of PFS:PPS for most women in the trial. A woman's PPS was typically 1.5 times her PFS, but estimates based on this ratio were imprecise and better explained in terms of a typical range (50% living for half to double the estimate), best case scenario (10% living beyond 4 times the estimate) and worst case scenario (10% dying within one sixth of the estimate).

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-09-02.
Abstract P5-10-02: Clinical Outcome of Two Sequences of Administering Paclitaxel (P) and Anthracyclines (A) as Primary Systemic Therapy (PST) and Adjuvant Chemotherapy (ACT) in Breast Cancer (BC) Patients: A Retrospective Analysis from the M. D. Anderson Cancer Center (MDACC)
Authors: Alvarez RH , Bianchini G , Hsu L , Cristofanilli M , Esteva FJ , Pusztai L , Buzdar AU , Hortobagyi GN , Valero V.
Published: April 2011

Background: P-and A-based regimens are widely used as PST and ACT of early BC. It is unknown whether the efficacy of such combinations is affected by their sequence of administration. The purpose of this retrospective analysis was to assess the clinical outcome of two different sequences of P and A in pts receiving PST and ACT.

Methods: We analyzed 3,010 pts (1,414 PST and 1,596 ACT) with stage I — III BC treated between 1994 -2009. These pts were identified through our prospective online MDACC breast cancer database. Pts treated with trastuzumab, docetaxel or adriamycin/cyclophosphamide-regimen were excluded. Pathological complete response (pCR) was defined as no residual invasive disease in breast and ipsilateral axillary lymph nodes.

Results: PST cohort included 1.071 pts (75%) with clinical stage I-IIIA and 343 (24.2%) stage IIIB-IIIC BC; 1,188 pts (84%) received the sequence P→A and 226 pts (16%) A→P. In the PST cohort 958 pts (67.7%) and 161 (11.3%) had hormone-receptor (HR) positive (+) and HER-2 + BC, respectively. ACT cohort consisted of 1,503 pts (94%) with pathological stage I-IIIA and 93 (5.82%) stage IIIB-IIIC. 1,196 pts (75%) received the sequence P→A, and 400 pts (25%) A→P. In the ACT cohort 1,122 (70.3%) and 93 (3.9%) had HR+ and HER2+ BC, respectively. Both cohorts of pts were balanced by HR-status, clinical stage, and menopausal status. The combined p-values for ACT and PST cohorts were calculated and they were significant for both RFS (p=0.022) and OS (p=0.002). In univariate analysis the sequence A→P was associated with inferior outcome. In Cox multivariate analysis, after stratification for period at diagnosis and adjustment for age, clinical stage, HR status, grade, and LVI the A→P sequence administered as PST was associated with significantly higher risk of relapse (HR 1.49; CI 1. 10-2.03; p=0.01) but not death (HR 1.28; CI 0.90-1.84; p=0.17). In the ACT cohort, the Cox multivariate analysis, after stratification for age, HR status, HER2 the sequence A→P was significantly associated with higher risk of death (HR 2.02; CI 1.33-3.06; p=0.001) but not relapse (HR 1.21; CI 0.82-1.79; p=0.33).

Conclusions: The P→A sequence compared to the A→P sequence is associated with lower risk of relapse and death in PST and ACT, respectively. This retrospective analysis is hypothesis-generating and should lead to a prospective randomized trial to compare the two sequences as PST or ACT in locally advanced or early BC, respectively.

Primary Systemic Therapy (N=1,414)

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-02.
Abstract P5-10-11: Ongoing Evaluation of Capecitabine-Based Therapy in Early Breast Cancer (EBC)
Authors: Poole C , Barrios C , O'Shaughnessy J , Martin M , Möbus V.
Published: April 2011

Background: Capecitabine (C) is an established agent in MBC & is being evaluated in anthracycline/taxane-based adjuvant (adj) & neoadjuvant (neoadj) regimens.

Methods: We summarise available data for C from randomised phase III studies in EBC.

Results: Significant efficacy benefits were reported with two C-based regimens in EBC: recurrence-free survival (RFS) was significantly improved when C was added to an adj regimen in the FinXX trial (3-year RFS: 93% vs 89% control; HR 0.66 [95% CI: 0.47-0.94]; p=0.02) [Lancet Oncol 2009;10:1145-51]. Pathological complete response (pCR) was significantly higher when C was integrated into a standard neoadj regimen in the ABCSG-24 study (24.3% vs 16.0% control; p=0.02) [ECCO-ESMO 2009; Abst 4BA]. Two studies were negative: one adj [Muss et al. NEJM 2009;360:2055-65] & one neoadj [GeparQuattro JCO 2010;2024-31].

D=docetaxel; Cyc=cyclophosphamide; E=epirubicin; F=5-FU; A=doxorubicin; P=paclitaxel; bev=bevacizumab; G=gemcitabine; M=methotrexate; DFS=disease-free survival; EFS=event-free survival

Safety data are available from 3 other adj studies: in the GEICAM trial, ED→C was generally well tolerated and associated with significantly better hair recovery than control (incomplete hair recovery: 28% ECyc→D vs 11% ED→C; p=0.0004); in the GAIN study, haematological toxicities were more common in the E→P→Cyc arm & discontinuations more frequent with ECyc→CP; in the ICE study in pts aged >65 yrs, a low incidence of grade 3/4 AEs was reported with C & significantly higher global QoL scores were attained with C vs control (week 20, p=0.008). Several phase III trials are ongoing (table): US Oncology is conducting a study in high-risk EBC, which will report efficacy data shortly; CIBOMA collaborative group is conducting a trial of C maintenance therapy after adj anthracycline/taxane in triple-negative EBC; the TACT2 study has a 2x2 factorial design in resected/operable EBC; safety data are expected from both studies: MINDACT is an EORTC/collaborative group study in node-negative EBC and compares a 70-gene signature with traditional methods of risk evaluation; pts with high-risk disease receive anthracyclines or CD.

Conclusions: The ongoing evaluation of C in EBC encompasses >20,000 pts. Following initial positive data for C in EBC, further results of these trials are eagerly awaited to define the clinical utility of C-based therapy in this setting.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-11.
Abstract P5-10-13: Phase I Dose Escalation Study of Pirarubicin in Combination with Cyclophosphamide in Breast Cancer
Authors: Sakata M , Jinno H , Hayashida T , Takahashi M , Sato T , Seki H , Shimada K , Nishiya S , Kitagawa Y.
Published: April 2011

Background: Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardialdysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. Pirarubicin is a more lipophilic derivative of doxorubicin, with a higher uptake rate of cells, lower cardiotoxicity and better antitumor efficacy in preclinical models.

Purpose: We conducted a single-institution phase I clinical trial to determine the maximum-tolerated dose (MTD) and define the toxic effects and recommended dose (RD) of pirarubicin in combination with cyclophosphamide in patients with breast cancer. Patients and Methods: Patients who had received prior anthracycline therapy were excluded. Cohorts of three patients with breast cancer were treated with escalating doses of pirarubicin (40 to 70 mg/m2) intravenously administered every three weeks in combination with cyclophosphamide (60 mg/m2) for 4 or more cycles.

Results: Eleven patients of stage I/II operable breast cancer received a total of 46 cycles of pirarubicin and cyclophosphamide as post-operative adjuvant chemotherapy. The most frequently reported treatment-related grade 2 adverse events were constipation (36%) and nausea (27%). There were no grade 3/4 events. Grade 2 leukocytopenia and grade 2 fatigue were dose-limiting at 70 mg/m2, the maximum-tolerated dose was 60 mg/m2. Grade 2 alopecia was reported in 60 and 70 mg/m2 pirarubicin group. Conclusion: At the MTD of 60 mg/m2 every 3 weeks, pirarubicin in combination with cyclophosphamide was associated with mild, reversible toxicity. The recommended phase II dose is pirarubicin 50 mg/m2 and cyclophosphamide 60 mg/m2 on day 1 every 21 days.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-13.
Abstract P5-10-14: Adjuvant Chemotherapy Treatment of Breast Cancer in Women 75 Years and Older
Authors: Kaplan HG , Malmgren JA , Atwood MK.
Published: April 2011

Background: Adjuvant chemotherapy is not generally recommended for women 75 years and over due to presence of comorbid conditions and lower stage.

Methods: We conducted a prospective cohort study of all women presenting with primary breast cancer (BC), aged 21-94, biopsy confirmed Stage 0-IV from 1990-2008 identified and tracked by our registry (n=8295). Clinical presentation characteristics including age, race, TNM stage, histologic type, surgical procedure, radiation and chemotherapy treatment were chart abstracted at diagnosis and follow up. Forward conditional stepwise regression was used to test for association significance for chemotherapy and the Kaplan-Meier method for disease free survival rate comparisons (DFS).

Results: Women aged 75+ represented 12% of patients in our community based cancer center registry database (n=962). No change in percentage of patients aged 75+ was seen over time. The majority of 75+ BC patients were stage 0-1 (63%) with 36% stage II-III (n=339). Initial patient treatment was 74% lumpectomy/radiation (n=708), 11% mastectomy/radiation, and 11 % mastectomy/no radiation. 82% were estrogen receptor positive and of these 76% were recommended treatment with hormone therapy. 70% of patients received an oncology consult and 8% (n=76) were recommended for chemotherapy. Of the 76 patients, 59 (78%) completed chemotherapy with incompletions due to complications of therapy (10), patient choice (4), unknown (1), other reason (1), and death (1). The most commonly given chemotherapy regimens were CMF (n=21), AC/Taxol (n=13), and AC (n=7) with 13 receiving an adriamycin containing regimen and 22 receiving non-standard therapy. In a conditional logistic regression model of TNM stage I-IV 75+ patients (n=847) with outcome=adjuvant chemotherapy, significant variables by order of entry into the model were 1) TNM stage, 2) Her2/neu status, 3) estrogen receptor status and 4) age at diagnosis. Chemotherapy treatment rates for 50-59 year olds were 51%, 60-64 = 40%, 65-69 = 28%, 70-74 = 19%, and 75+ = 8% (Pearson chi square = 687.78, p<.001). DFS was equivalent for 75+ stage 0-I BC patients compared to 50-74 year olds, with a lower DFS rate among 75+ stage II-III patients (stage II: log rank test=10.21, p=.001, stage III: log rank test=4.14, p=.042).

Conclusions: TNM stage was the predominant factor in deciding to treat patients 75+ with adjuvant chemotherapy. Stage 0-I patients age 75+ and 50-74 had equivalent survival. Stage II-III age 75+ patients had significantly worse DFS than age 50-74 patients. There is an urgent need to identify effective and tolerable treatment regimens for stage II-II BC patients 75 years and older.

Figures available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-14.
Abstract P5-10-19: The Influence of Time to Completion of Chemotherapy on Survival in Patients with Triple Negative Stage III Breast Cancer
Authors: De Los Santos J , Hinton B , Carpenter J , LoBuglio A , Falkson C , Keene K , Meredith R , Krontiras H , Bland K , Wang C , Kim Y , Forero A.
Published: April 2011

Background: Neoadjuvant chemotherapy is increasingly delivered to facilitate breast conserving surgery through tumor downstaging. Prospective trials of neoadjuvant chemotherapy from the NSABP suggest no difference in survival outcomes in patients receiving neoadjuvant versus adjuvant therapy; however, subset analysis in 2 combined trials (B-18 and B-27) demonstrated a trend in DFS improvement in young patients (<50 yrs), who often have more aggressive variant tumors. This study explores the possibility that patients with aggressive variant molecular subtypes [triple receptor negative (TN)] treated with modern chemotherapy, may significantly benefit from earlier completion of drug delivery. Methods: Billing codes for all breast cancer patients treated with chemotherapy between 1/1998 and 5/2005 at the University of Alabama at Birmingham were reviewed to comprehensively capture all Stage II and III patients with intact data. Patient, tumor, and treatment related variables were recorded and patients were divided to 4 molecular subtypes based on receptor status: hormone receptor (HR) positive, Her2 negative; HR+/− , Her2+; and triple receptor negative (TN). Kaplan Meier curves to assess survival were performed by dividing the TN group into 2 groups: those completing chemotherapy ≥5 vs > 5 months from diagnosis. Results: 409 patients with Stage II-III disease with were identified: 124 received neoadjuvant and 285 received adjuvant chemotherapy. Out of this group, 81 patients had TN breast cancer (60 Stage II and 21 Stage III). Median age was 49 years. Median follow-up was 72 months. Chemotherapy consisted of adriamycin, taxol and cytoxan for a median of 9 cycles. Stage III patients who completed chemotherapy within 5 months had a statistically significant improvement in OS and DFS (p=0.03), and had a trend towards improvement in DMFS (p=0.10) when compared with those who took longer than 5 months to complete chemotherapy. Conclusion: Completion of chemotherapy in a shorter time interval in patients with Stage III, TN breast cancers was associated with an improvement in DFS and OS. Consideration of timing of chemotherapy warrants further study.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-19.
Abstract P5-10-23: Frequency and Cost of Chemotherapy-Related Serious Adverse Effects in a Canadian Population Sample of Women with Estrogen and/or Progesterone Receptor Positive Early Stage Breast Cancer
Authors: Hannouf MB , Brackstone M , Zaric G.
Published: April 2011

Background: Chemotherapy-related serious adverse effects (CSAE) reported by clinical trials of chemotherapy and by population-based assessments of CSAE in breast cancer populations with different clinicopathological characteristics may not reflect the experiences of women with estrogen and/or progesterone receptor positive (ER+/PR+) early stage breast cancer (ESBC). We aimed to characterize the risks and economic impact of CSAE among women in the Canadian general population treated with chemotherapy for ER+/PR+ ESBC. Methods: We used the Manitoba Cancer Registry to identify all women (n=665) diagnosed with ER+/PR+ ESBC during the period from January 1, 2000 to December 31, 2002. One-year of follow-up information from diagnosis, including hospitalizations and emergency room visits for all adverse effects that are typically related to chemotherapy, were identified by linking with Manitoba Administrative Databases including the Hospital Discharge Database and the Physician Claims Database. 251 women received chemotherapy during the 12 months after the initial diagnosis with ESBC. Hospitalizations or emergency room visits for CSAE and health care expenditures were compared between women who did and did not receive chemotherapy. We assessed the effect of chemotherapy on rate of CSAE using logistic regression, adjusting for menopausal status, lymph node status, anthracycline-containing chemotherapy agents, and comorbid indices. All statistical tests were two-sided.

Results: Women who received chemotherapy were more likely than those who did not to be hospitalized or visit an emergency room for CSAE (2.6% versus 9%, mean difference =6.4%, 95% CI=3.5% to 10%, p=0.01). In a logistic regression analysis, the rate of CSAE was found to be significantly greater for women with post-menopausal status (post-versus pre-menopausal, odds ratio 2.4; CI= 1.7 to 2.8) and 1-3 lymph node positive (LN+) (0 versus 1-3 LN+, odds ratio, 3.1; CI= 2.5 to 3.6). Chemotherapy recipients incurred large incremental expenditures for CSAE (pre-menopausal LN-: $1100 per person per year; post-menopausal LN-: $1600 per person per year; post-menopausal 1-3 LN+: $2200 per person per year).

Conclusions: The impact and costs of CSAE among ER+/PR+ ESBC are larger than predicted from clinical data and vary significantly by lymph node and menopausal status. Our findings, when combined with recent population-based data suggesting that women with ER+/PR+ ESBC may not gain benefit from chemotherapy as much as reported in clinical trials, have important implications for quality of life and could affect decisions regarding the use of chemotherapy in these patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-23.
Abstract P5-11-07: ER Positive Screen Detected Breast Cancers (SDBC) Do Not Require Chemotherapy
Authors: Bundred NJ , Morris J , Cheung S , Knox WF , Lawrence G.
Published: April 2011

Background: Meta-analysis of symptomatic breast cancer trials advises chemotherapy to women less than 70 years of age at high risk of death (i.e benefit of >1% survival benefit from treatment) but UK screen detected breast cancers (SDBC) in women aged 50 to 65 years have a 97.2% relative survival compared to 77.6% for symptomatic cancers in the ABS at BASO audit.

Methods: To determine which women benefit from chemotherapy, we have analysed 1,607 symptomatic and SDBC in one unit. Results: SDBC had a significantly lower risk of relapse with the five year breast cancer mortality for ER positive breast cancers being low in the Excellent, Good and Moderate Prognostic Group 1 but being significantly higher in the Good Prognostic Group and Moderate Prognostic Group 1 diagnosed symptomatically. Symptomatic cancers in the Good Prognostic Group (GPG) and Moderate Prognostic Group 1 (MPG1) had a hazard ratio of 5.34 (1.61-17.75) and 14.46 (10.4-106.0) respectively for cancer death compared to SDBC.

NPI Index Score and Mortality in SDBC and Symptomatic Cancers treated in Manchester 1990-98 - ER

ER positive cancers detected by screening (but not ER negative) had a 0.6% mortality annually whereas the symptomatic cancers had a 10% annual mortality in the first five years. The UK National ABS/BASO Audit was used to confirm the findings (Table 2).

Data over the last ten years of follow-up from the ABS at BASO audit indicates significant survival improvements in the Moderate Prognostic Group 2 (MPG2) and the Poor Prognostic Group (PPG) for SDBC.

NHSBSP and ABS at BASO Breast Screening National Audit Data for Invasive SDBCs diagnosed between 1990 and 2002

Discussion: Thus, ER positive SDBCs represent a group which have a low risk of relapse and do not require chemotherapy. The improvements in survival of SDBC relate to better treatment of ER negative and HER2 positive breast cancers and have occurred predominantly in the MPG2 and PPG.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-07.
Abstract P5-11-14: Distribution of Tamoxifen and Five Metabolites into Normal and Malignant Human Breast Cancer Tissue during Conventional and Low Dose Treatment
Authors: Gjerde J , Gandini S , Guerrieri-Gonzaga A , Hauglid Flågeng M , Bonanni B , Macis D , Mellgren G , De Censi A , Lien EA.
Published: April 2011

Background: Biotransformation of tamoxifen leads to metabolites with different pharmacological and toxicological effects. Profiling and screening for active metabolites are important to assess their contribution to the overall therapeutic and adverse effects. The anticancer effect of tamoxifen is believed to be due to the hydroxylated metabolites 4hydroxytamoxifen (4OHtam) and 4hydroxyNdesmethyltamoxifen (4OHNDtam, endoxifen). Its demethylated metabolites have been related to side effects of the drug, whereas effects of tamoxifenNoxide (tamNoxide) have not been evaluated. In the present study we wanted to examine the distribution of tam and five of its metabolites in serum and normal and malignant breast tissues during normal dose (20 mg/day) and low dose (5 or 1 mg/day) regimens after 28 days of continuous dosing.

Methods: Serum and biopsies from 56 patients were available for analysis. The concentrations of tamoxifen and the metabolites 4OHtam, 4OHNDtam, Ndesmethyltamoxifen (NDtam), Ndesdimethyltamoxifen (NDDtam), and tamNoxide in serum and tissues were measured by means of a recently developed highly sensitive liquid chromatography tandem mass spectrometry (LCMSMS) method.

Results: Serum and biopsies from 56 patients were available for analysis. All compounds including the potent metabolites 4OHtam and 4OHNDtam were detected and measured in all samples. The tissue levels of tam and its hydroxylated and demethylated metabolites were highly related to the serum levels (p < 0.000 — 0.0069). The tumor tissue to serum concentration ratios of tamNoxide decreased by increasing doses (p < 0.0001) whereas this ratio was unchanged over the dose range 1-20 mg/day for the other compounds measured.

Conclusion: Tamoxifen and its metabolites were detected in all samples examined including those sampled during the low dose regimens. The tissue levels of tamoxifen and its hydroxylated and demethylated metabolites were strongly corresponding to the serum concentrations, in contrast to those of tamNoxide. The strong relations between the concentrations of the potent active 4OHtam and 4OHNDtam (endoxifen) in serum and target tissues suggest that implementation of therapeutic drug monitoring may represent a tool to improve tamoxifen therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-14.
Abstract P5-13-02: Impact of Adjuvant Trastuzumab on Local Regional Recurrence: Data from the NCCTG N9831 Study
Authors: Halyard MY , Dueck AC , Pisansky TM , McLaughlin SA , Pierce LJ , Marks LB , Solin LJ , Pockaj BA , Perez EA.
Published: April 2011

Background: Trastuzumab (H) improves disease-free survival (DFS) in patients (pts) with HER2 positive breast cancer (BR Ca) when used with adjuvant chemotherapy. We herein compare the rates of local regional recurrence (LRR) in pts randomized to adjuvant chemotherapy with or without adjuvant H.

Methods: The phase 3 randomized trial NCCTG N9831 enrolled 3505 pts with high risk HER2 positive Br Ca to evaluate the effect of adjuvant H on DFS. Pts were randomized to either doxorubicin (A) and cyclophosphamide (C) followed by paclitaxel (T); or AC→TH→H. RT was given concurrently with H after ACT chemotherapy. Pts analyzed underwent lumpectomy (L) + radiotherapy (RT), mastectomy (M) alone, or M+RT. All pts underwent sentinel lymph node biopsy alone and/or axillary dissection. 2816 pts were eligible for competing risk analysis of LRR as a first event (competing risks were distant recurrence, contralateral Br Ca, second primary cancer, or death). Median follow-up is 5.3 years.

Results: Primary breast therapy included L+RT 1062 (38%), M 711 (25%), and M+RT 1043 (37%). Axillary dissection was performed in 90% of pts but less frequently with L+RT (83%) compared to M (88%) or M+RT (98%), chi-sq P<0.001. Stage at presentation was I 41%, II 51%, and III 8% with a significant greater proportion of higher stage pts undergoing M+RT, chi-sq P<0.001. Overall the 5-year LRR rate was 4.1% (95% CI 3.5-4.9%) and similar among the treatment groups: L+RT 4.7% (95% CI 3.6-6.1%), M 3.5% (95% CI 2.4-5.1%), and M+RT 2.3% (95% CI 1.6-3.4%). Among pts with a LRR, 66% were local recurrence only, 11% were local-regional, and 23% were regional only. In the L+RT patients with a LRR, the corresponding rates were 74%, 7%, and 19%, respectively. In the M patients with a LRR, the corresponding rates were 40%, 23%, and 37%, respectively. In the M+RT patients with LRR, the rates were 79%, 4%, and 17%, respectively. H is associated with a non-statistically significant reduction in the risk of LRR for pts who receive L+RT or M+RT (Table 1). No such trend was seen in the M alone group but the number of events was low.

Table 1. LRR According to Local and Adjuvant Treatment Groups

Conclusion: The LRR as the first reported site of failure was low with a median 5. 3 year follow-up. Adjuvant H was associated with a trend of lower LRR in the pts treated with L + RT or M+RT. This observation suggests an additive effect of RT and H on LRR that warrants further investigation. The small number of local-regional events in this one randomized trial supports further investigation of LRR across other adjuvant trastuzumab trials.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-02.
Abstract P5-13-04: Use of Bisphosphonates in the Adjuvant Setting for Breast Cancer — A More Than 10 Years Single Centre Experience
Authors: Jakob A , Groh U , Schwoerer D , Schattenberg A , Siebers JW.
Published: April 2011

Background: Adjuvant therapies for early breast cancer are associated with substantial decrease in bone mineral density. Bisphosphonates are antiresorptive agents that have an established role in preventing skeletal morbitity in patients with bone metastases and in the treatment of osteoporosis. It has also been shown that these agents are active in preventing cancer treatment induced bone loss in women with early stage breast cancer. Recently, several trials have demonstrated that bisphosphonates may exert anticancer effects in the adjuvant setting. Patients and methods: Since 1997 we treated an increasing number of unselected patients with early breast cancer with bisphosphonates (up to 2009: 1144 out of 1876 patients). There was no significant difference in the two patient groups concerning tumour size, nodal status, hormone receptor (HR) expression, HER-2 expression and adjuvant treatment modalities. In most cases we used zoledronic acid, but also clodronate ibandronate or alendronate.

Results: Disease-free survival (DFS) was significant better in patients treated with bisphosphonates (p = 0.009). This was also true in the subgroup of patients with hormone receptor positive disease (p=0.0011) and even more striking in patients with N+ disease (p=0.00003). There was no significant difference in DFS in patients with hormone receptor negative disease. In our analyses especially patients with N+ and ER/PR+ disease showed a significant advantage from treatment with bisphosphonates. Conclusion: This large single centre experience demonstrates a significant improvement of disease-free survival in patients with breast cancer treated with bisphosphonates in the adjuvant setting. The benefit was more pronounced in the subgroup of nodal positive and hormone receptor positive disease.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-04.
Abstract P5-13-06: Survival Benefit of Bisphophonates in Early Breast Cancer: A Meta-Analysis
Authors: Lin Y , Ying X , Wang F , He P.
Published: April 2011

Objectives: Bone is one of the most common metastatic sites of breast cancer. Recent date from randomized clinical studies suggested that the use of bisphophonates affect bone metastasis and survival in early breast cancer patients. Results from some of these trials are encouraging but somewhat contradictory. We conducted a meta analyses to assess the effect of bisphosphonates on bone metastasis and survival in primary breast cancer patients.

Methods: Trials were retrieved by searching the PubMed database, Cochrane Library and major cancer scientific conferences up to January 2010. All tirals randomized patients to receive any bisphosphonate versus non-use or placebo. Hazard ratios (HR) and its 95% CIs for bone metastasis free survival and overall survival were estimated.

Results: 8 eligible trials including 6132 patients entered the analysis. 3049 patients were treated with bisphosphonates and 3083 received either placebo or no treatment. Compared with no use, bisphophonates in the adjuvant setting improved the overall survival (HR=0.808; 95%CI 0.708-0.923; P = 0.022). However, the reduction of bone metastasis was failure to be seen (HR = 1.011; 95% CI 0.996-1.027; P = 0.667). Conclusion: Our meta-analysis provides additional evidence that adjuvant breast cancer treastment with bisphosphonates brought a survival benefit. However, the result should be carefully interpreted for that the statistical significance was not consistent in the bone benefit. Results of new clinical trials were awaited.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-06.
Abstract P5-13-07: Hormone Levels in the OPTION Trial Show No Ovarian Protection by Goserelin in Adjuvant Chemotherapy for Early Breast Cancer — An Anglo-Celtic Collaborative Group and NCRN Trial
Authors: Leonard R , Adamson D , Anderson R , Ballinger R , Bertelli G , Coleman R , Fallowfield L , Keerie C , McLinden M , Mansi J , Thomas G , Yellowlees A.
Published: April 2011

Non-randomised data suggest a protective benefit on ovarian function for using GnRH analogues to suppress menses during chemotherapy. However there have been no published randomised clinical trials to date that confirm this protection indicated by recovery of menstrual function.

Observational data suggest that patient age and cumulative dose of alkylating agent or selection and intensity of dose other agents such as anthracyclines or taxanes are also important variables that determine the risk of chemotherapy-induced premature ovarian failure (POF). This trial in premenopausal women has tested the effect of goserelin (G) given randomly before and during adjuvant chemotherapy in premenopausal women with breast cancer. Any standard regimen was allowed but women were randomised in 2 strata, under 40 yrs and over 40 yrs at diagnosis. 227 patients were recruited by end December 2009, and 173 met the criteria for 1 year follow-up for this analysis; 140 patients of these 173 patients had provided adequate data on menstrual bleeding; 87 patients were aged under 40 and 53 patients were aged over 40 at the time of chemotherapy. Cessation of menstruation during chemotherapy was defined as at least two consecutive cycles with no menstrual bleeding since the previous cycle. Additionally, prior to the final cycle of chemotherapy, there had to be no return of menstrual bleeding. Of those patients who had ceased periods during chemotherapy, those with no further menstrual bleeding at 12 months follow up were deemed to have reached menopause. Patients were randomised to receive G or no G at start of chemotherapy. Primary endpoint was recovery of menses at 12 months from start of chemotherapy. Secondary endpoints included quality of life, oestrogen/LH/FSH levels at start and completion and at 12 months along with anti-mullerian hormone (AMH, as an indicator of impending ovarian failure). Endocrine data over time showed a close correlation with menses in that both measures indicated no protective effect in the treatment group. There was no significant difference with respect to POF when all patients were considered. However there was a trend to poorer recovery of menstrual function at 12 months in the under-40 yrs group who had G with 34.7% having POF in the G treated group and 15.8% in the chemotherapy only treated group (P ≥0.05). This is mirrored by the oestrogen data which show an incomplete recovery at 12 months of oestrogen in the G group compared with controls although a complete recovery at 24 months. LH and FSH levels showed appropriate suppression by G and thereafter similar levels to controls. Early follow up data on the hormone levels shows no difference between the treatment groups.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-07.