bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast epithelial differentiation is altered in BRCA1mut/+ carriers prior to the onset of cancer and contributes to the basal tumor phenotype.
Authors: Keller P , Gupta PB , Klebba I , Gilmore H , Come S , Schnitt S , Lander ES , Kuperwasser C
Published: December 2010

Abstract #3083

Human breast tumors are broadly divided into either luminal-like or basal-like cancers. This distinction is significant since basal-like tumors are more aggressive and afford a poor patient prognosis relative to luminal-like tumors. For reasons that are unclear, germline mutations in BRCA1 strongly predispose for poor prognosis basal-like tumors. The predisposition for basal-like tumors in BRCA1mut/+ patients could be due to (1) differences in underlying target cell populations between BRCA1mut/+ and BRCA1+/+ women or (2) differences in the genetic mutations arising within a single shared target cell type. This basic question has remained unresolved due to a lack of experimental models in which it can be addressed. We describe here a novel in vivo breast cancer system that enables the generation of tumors by introducing oncogenes into normal breast epithelium derived directly from human breast tissue. This system is unique in that it enables human-derived epithelial cells to be sorted for cell surface markers and transformed without requiring in vitro culture prior to implantation in vivo. Using this experimental system, we show that epithelial cells from BRCA1mut/+ patients give rise to tumors that exhibit multiple features of basal differentiation, in contrast to epithelial cells transformed with identical oncogenes from BRCA1+/+ patients. We show further that non-cancerous epithelial cells from BRCA1mut/+ patients already exhibit atypical differentiation even prior to the onset of cancer, in contrast to cells from BRCA1+/+ women. Remarkably, some of these differences are observable in the context of unperturbed breast tissue obtained from disease-free BRCA1mut/+ and BRCA1+/+ patients. Collectively, these findings show that the increased incidence of basal-like tumors in BRCA1mut/+ patients is a reflection of the altered differentiation of breast epithelial cells in BRCA1mut/+ patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3083.
Is the biology of breast cancer changing? A study of hormone receptor status and grade of breast cancers 1984-1986 and 1996-97.
Authors: Brown SB , Mallon EA , Edwards J , McGlynn LM , Campbell FM , Timothy CG
Published: December 2010

Abstract #3088

Introduction: There has been a significant improvement in breast cancer survival in the UK in recent decades. Changes in the molecular epidemiology of breast cancers may have contributed to this, but the existing evidence may be confounded by heterogeneity of laboratory protocols. This study aimed to re-analyse the molecular profile of breast cancers from two different time periods using archived tissue. Methods: Archived tumour samples from all breast cancer patients at two Glasgow hospitals between 1984-86 and 1996-97 were sought, and linked to clinicopathologic, screening, demographic and survival data. Patients in the 1984-6 cohort would not have been offered mammographic screening but those in 1996-97 would have. Samples were placed in tissue microarrays and underwent immunohistochemistry for ER, PR and Her-2 status with strict standardisation. H&E sections were constructed to assess tumour grade. Statistical analysis included Kaplan-Meier survival analysis and Cox's regression. Results: 900 tumour samples underwent staining. In 1984-86, 8% of tumours were grade 1 and 42.9% grade 3 but in 1996-97 14.9% were grade 1 and 36.8% grade 3 (p=0.009). This effect appeared to be exerted by the presence of screen detected tumours in 1996-97 (p for difference in grade distribution between symptomatic patients between 1984-86 and 1996-97 = 2). In 1984-86 64.2% of tumours were ER positive and in 1996-97 71.5% were ER positive (p=0.042). This did not appear to be a function of the screening programme as there was a significant rise in ER positivity in symptomatic patients between the two cohorts (p=0.024). 44.9% of tumours in 1984-86 and 49.9% of tumours in 1996-97 were PR positive (p=0.181). 21.5% of tumours in 1984-86 and 20.6% of tumours in 1996-97 were Her-2 positive (p=0.772). 5-year survival in 1984-1986 patients was significantly lower than in 1996-1997 patients (p<0.001). When the effect of cohort on survival was adjusted for these changes in ER status and grade, cohort remained a significant independent factor. Conclusions: This study suggests a small but significant rise has occurred in the incidence of ER positive tumours in women in Glasgow. There has also been a shift in grade distribution of tumours, which is likely to be an effect of the NHS screening programme. The changes do not fully explain improvements in breast cancer survival but should be borne in mind when applying the results of clinical trials performed in the past to the women of today.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3088.
Effect of protein phosphatase 2A subunit gene haplotypes and proliferative breast disease on breast cancer risk.
Authors: Dupont WD , Breyer JP , Bradley KM , Schuyler PA , Plummer W , Sanders ME , Page DL , Smith JR
Published: December 2010

Abstract #3090

Background: A large number of genes encode components of complex growth factor signaling networks and may contribute to breast cancer risk. Prominent among these candidates are protein phosphatases that counter kinases of signaling cascades. We explored the role of a set of candidate genes encoding subunits of the major cellular protein phosphatase 2A (PP2A) in a cohort of women with a history benign breast disease. Women with a history of benign proliferative breast disease are at increased risk of subsequently developing breast cancer.  Materials and Methods: We evaluated genetic variation in a set of 49 candidate genes of signal transduction pathways for potential contributions to breast cancer risk. The study was conducted as a nested case-control investigation of a cohort of women with a history of benign breast disease. DNA prepared from the original archival benign breast biopsy was available for 301 women diagnosed with breast cancer on follow-up, and for 545 of their 602 matched controls. Controls were women who remained free of breast cancer, matched to cases in a 2:1 ratio by race, age, and year of entry biopsy.  Results: We observed that a PP2A structural subunit gene, PPP2R1A, and two regulatory subunit genes, PPP2R2A and PPP2R5E, each appeared to modify breast cancer risk with both risk-elevating and risk-reducing genetic variants. Only PPP2R2A was significantly associated with breast cancer after correction for multiple comparisons, with significant risk and protective haplotypes (OR = 1.79, study-wide P = 0.015, and OR = 0.62, study-wide P = 0.025, respectively). These variants interact with a history of proliferative breast disease to modify risk for breast cancer. In a dose model that included all three genes, breast cancer risk ranged from a 5.1-fold decrease to a 3.9-fold increase in risk, depending on the portfolio of variants inherited by a woman (study-wide P = 0.02).  Discussion: If confirmed by independent studies, PP2A may play a key role as a tumor suppressor in breast cancer that is able to augment as well as to nullify elevated risk associated with early benign proliferative breast disease.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3090.
Impact of BRCA mutation status on the clinical phenotype and survival of hereditary breast cancer.
Authors: Kiechle M , Engel C , Schwarz-Boeger U , Grund D , Preisler-Adams S , Crohns C , Stark S , Gadzicki D , Strunz K , Schoenbuchner I , Nestle-Kräemeling C , Kast K , Ditsch N , Schlehe B , Schmutzler R
Published: December 2010

Abstract #3091

Background : In a multidisciplinary program supported by the German Cancer Aid in 1996-2006 a total of 3.408 women with a family history for breast and/or ovarian cancer were genetically counselled and tested for BRCA-1 and BRCA-2 mutations.  Methods: The mutations were detected using DHPLC and direct sequencing. The family history of breast and/or ovarian cancer was proven by collecting medical reports of family members. The statistical analysis was done using standard procedures (Kaplan-Meier-analysis, t-test, chi-square-test).  Results: Among the women with breast cancer 566 showed a deleterious BRCA1 and 313 a BRCA2 mutation. Four women were found to have mutations in both genes and 2.525 were BRCA-1/2 negative. In accordance with the literature we found the phenotype “hormone receptor negative and grade 3” as well as the medullary subtype significantly more often in BRCA1 associated breast cancers (74% vs. 24%, 63% vs. 42% and 10% vs. 5%). The median age of onset was significantly lower in BRCA1 mutation carriers (38 yrs) compared to BRCA2 mutation carriers (45 yrs) and women tested negative for BRCA1 and BRCA2 mutations (46 yrs) as well as sporadic breast cancer cases within these families (52 yrs). The median age of the 4 women with mutations in both genes was even lower (median age 33.5 yrs). Although BRCA2 associated breast carcinomas presented in more advanced stages (N+ in 44%[118/257] compared to BRCA-1 positive in 31%[166/519], p<0.01) there was no difference in overall survival between BRCA1 and BRCA2 mutation carriers. However, BRCA1 and BRCA2 negative cases showed a significantly better survival rate compared to the women with mutations (p<0.0001). Women from families with early onset breast cancer (<35 yrs) or bilateral breast cancer (<40 yrs) had a significantly better survival (p<0.0001) than women from families with a later age of onset.  Conclusions: The BRCA mutation status has a significant impact on the clinical phenotype of hereditary breast cancer which is important for the clinical management, counselling and prevention.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3091.
Evaluation of variants in BRIP1, PALB2 and CHEK2 in a west of Ireland breast cancer cohort.
Authors: Mc Inerney NM , Miller N , Rowan A , Colleran G , Curran C , Ian T , Eli S , Michael KJ
Published: December 2010

Abstract #3092

Introduction  Positive family history is the most important risk factor in breast cancer predisposition. Recent studies have identified variants in BRIP1, PALB2 and CHEK2, which have been proposed as breast cancer susceptibility genes conferring an increased relative risk of 2-4%.  Aims  To evaluate the role of the above variants in the West of Ireland population and to examine their potential clinical relevance.  Methods  Proposed candidate genetics variants in BRIP1, PALB2 and CHEK2 were interrogated in 192 patients with a high risk of familial breast cancer. Genescan analysis and direct sequencing were used to evaluate these variants. Where a variant was exhibited, it was then examined further in 990 sporadic breast cancer patients and 1016 matched non-cancer controls using KASPar genotyping technology.  Results  We demonstated mutations in BRIP1 and CHEK2 genes. 1 mutation was found in BRIP1 2392C→T in our 192 patients with a high risk of familial breast cancer. 5 breast cancer patients and 1 control exhibited a CHEK2110delC mutation within 990 breast cancer patients and 1016 matched non-cancer controls. Mutations previously demonstrated in PALB2 were not evident in 192 high risk patients.  Conclusions  We have confirmed the presence of variants in BRIP1 and CHEK2, candidate moderate penetrance genes, in breast cancer patients with a strong family history of breast cancer. This may have implications in clinical practice as our knowledge of these variants expands. The absense of PALB2 variants in patients at high genetic risk points to a low clinical significance. Our findings contribute to a better understanding of inherited breast cancer risk while helping to optimize future screening, therapeutic and prophylactic programs.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3092.
The new understanding of two-sided role of glutathione S-transferase M1 in breast cancer susceptibility.
Authors: Yu K , Di G , Wu J , Shao Z
Published: December 2010

Abstract #3098

[Background and purpose] Although glutathione S-transferase M1 (GSTM1) enzyme occupies a key position in biological detoxification processes by catalyzing the glutathione conjugation of carcinogens, GSTM1 gene is genetically deleted (referred as GSTM1-null or GSTM1-/-) in a high percentage of the Eurasian populations. Numerous studies have examined the association of GSTM1-/- with breast cancer yielding inconsistent results. In addition, few genetic variants in this gene have been explored. We set out to systematically evaluate the contributions of GSTM1 gene deletion/presence and common variants in GSTM1 to breast cancer, followed by functional studies.  [Methods and Results] In the present study, we show that GSTM1-/- does confer a weak increased risk of breast cancer compared with GSTM1-present genotype, being confirmed by a meta-analysis of combining 40 related studies with the current case-control study (921 cases vs. 711 controls) of Chinese population (overall odds ratio of 1.10, 95% confidence interval: 1.04-1.15, P<0.001). Unexpectedly, GSTM1 homozygous wild-type (+/+) is also associated with a risk of breast cancer compared with heterozygous (+/-) individuals on the basis of accurate classification using long-PCR-based assay. Furthermore, for the population with one allele of GSTM1 (GSTM1+/-) accounting for 30-50%, we genotype four common single nucleotide polymorphisms (SNPs) spanning GSTM1 gene and identify a functional variant g.-498C>G in the putative promoter region associated with breast cancer risk. It displays that minor -498G allele is significantly more frequent in breast cancer controls than in cases (odds ratio of 0.51, 95% confidence interval: 0.30-0.86, P=0.012). This allele also leads to significantly reduced promoter activity compared to the major -498C allele. Further studies reveal the -498G can modify AP-2 binding site and decrease GSTM1 transcription. Among the three AP-2 isoforms, AP-2α provides the predominant regulation effect on this SNP.  [Conclusions] These results indicate that the effect of GSTM1 genotypes conferring to breast cancer susceptibility is not dosage-dependent as taken for grant previously. GSTM1 has a two-sided role in breast cancer susceptibility; too high or too low expression of GSTM1 is not beneficial. We recommend that the complicated genetic predisposition of GSTM1 be considered when predicting breast cancer susceptibility using single or a panel of genetic variants.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3098.
HER2/ER subtypes associated with patient and tumor factors and predicted survival among participants in a retrospective breast cancer cohort study in Southern California.
Authors: Haque R , Press MF , Polikoff JA , Avila CC , Enger SM
Published: December 2010

Abstract #3099

Background: Molecular marker expression analyses have led to the identification of unique breast cancer subtypes that have clinical and prognostic importance. Using data from a large population-based breast cancer cohort, we report results examining combined HER2/neu and estrogen receptor (ER) subtype distribution in relation to patient and tumor characteristics as well as breast cancer specific survival.  Methods: We conducted a retrospective cohort study of 1,645 female members of a large managed care organization newly diagnosed with invasive breast cancer from 1988 to 1995. We collected patient, tumor, treatment, and outcome information from medical records and electronic cancer registry files. We used immunohistochemistry techniques to evaluate gene expression of specific molecular markers including HER2/neu and estrogen receptor (ER). We examined prevalence of markers as well as odds ratios (OR) and 95% confidence intervals (CI) comparing outcomes by marker expression.  Results: Women with HER2+/ER- tumors were more likely to have been diagnosed at a younger age (less than age 60) than women with luminal A subtype (HER2-, ER+ and/or PR+) tumors (65.5% versus 47.8%, P<0.0001). A higher proportion of women with HER2+/ER- tumors were other than white race compared with women with luminal A subtype (21.8% versus 11.6%, P=0.007). Women with luminal B (HER2+, ER+ and/or PR+) or basal-like (HER2-, ER-, PR) subtype tumors were similarly more likely to be older at diagnosis and from minority backgrounds than women with luminal A subtype. Family history of breast cancer was not clearly associated with HER2/ER subtype. Women with luminal A tumors were more likely to be diagnosed with stage 1 disease than women with other tumor subtypes (luminal A: 56.3%; luminal B: 38.9%; basal-like: 38.1%; HER2+/ER-: 25.5%; P<0.0001). Residual tumor in surgical margins was not associated with HER2/ER subtype. Compared with women with luminal A tumors, women with HER2+/ER- tumors were much more likely to die of their cancers overall (OR=6.5, CI=3.5-11.9), and by stage (stage 1: OR=11.5, CI=2.6-50.3; stage 2: OR=3.8, CI=1.6-9.2; stage 3/4: OR=9.0, CI=1.1-77.2). Odds of breast cancer death, overall and by stage, was also increased for women with luminal B and basal-like subtype tumors compared with women having luminal A subtype.  Conclusions: HER2/ER subtype was clearly associated with patient as well as tumor characteristics in this large cohort of breast cancer patients. Specific tumor subtypes (HER2+/ER-, luminal B, and basal-like) were also associated with increased likelihood of dying of breast cancer. Further work is warranted to define treatment strategies by molecular subtypes.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3099.
Preference for breast cancer risk reduction hormonal therapy in women age 50-69 years attending screening mammography.
Authors: Lupichuk SM , Currie GR , Bryant HE
Published: December 2010

Abstract #3100

Background: It is expected that tamoxifen, raloxifene and aromatase inhibitors (AIs) will become available for the indication of breast cancer prevention in postmenopausal women. It is unknown how women weigh the benefits and disadvantages of these drugs. The aim of this study was to elicit preferences, using a discrete choice experiment (DCE), for attributes of breast cancer risk reduction hormonal therapies amongst women age 50 – 69 years who attend screening mammography.  Methods: 500 potentially eligible women were randomly sampled from a screening mammography database (SMD). Women permitting contact from the investigators were invited to participate. Demographic and breast cancer risk factor data was collected from the SMD for participants and non-participants, and compared. The DCE was administered via a postal survey. The attributes and levels for the DCE are outlined in Table 1. A fractional factorial design and matched fold-over technique yielded 16 choice sets. Two dominant choice sets were added. For each choice set, respondents were asked to mark preference for Drug A, Drug B or Neither. The DCE was analyzed using conditional logistic regression (CLR). Regression post estimation calculations (RPECs) were used to predict chemoprevention uptake.    Results: 111 women agreed to be contacted by the investigators, 94 agreed to be sent a survey and 79 returned a completed questionnaire. The proportions of participants who were nulliparous or had a predicted 5-year breast cancer risk >1.66% were significantly higher than for non-participants (p<0.05). No differences were found for age, education or mammographic breast density. From the CLR, all attributes, except decreased risk bone fracture, had coefficients that were significantly different from zero (p<0.01) and of the expected sign. RPECs suggest that the uptake of tamoxifen, raloxifene and AIs would be 13%, 50% and 23% respectively, and that 14% would not consider chemoprevention.    Conclusions: The most important attribute in women's selection of a prevention drug was breast cancer risk reduction. However, the following attributes were still important negative influences on choice: increased risk bone fracture > endometrial cancer > venous thromboembolic event >> cost. Raloxifene may be favoured if all three agents were available.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3100.
Skin thickness as a measure of breast lymphedema.
Authors: Degnim AC , Hoskin TL , Cheville AL , Miller JP , Gamble GL , Baddour LM , Donohue JH , Thomsen KM , Maloney SD , Boughey JC
Published: December 2010

Abstract #3103

Introduction: Lymphedema is well-known in the arm but can also occur in the breast. Diagnosis is currently non-standardized and based on clinical impression. We sought to determine if skin thickness could serve as a useful measure in the diagnosis of breast lymphedema (BLE).  Methods: Patients undergoing unilateral non-mastectomy procedures were enrolled on this prospective clinical study preoperatively and evaluated for signs and symptoms of lymphedema in the operated breast in the postoperative period. Patients with established BLE were also studied. BLE diagnosis was independent of ultrasound findings and was based on a graded physical exam targeting clinical signs of edema and erythema. Skin thickness was measured with ultrasound at the 6 o'clock position of both breasts. Differences in skin thickness were assessed by the ratio of skin thickness in the operated and contralateral breasts, with comparison of means by two-sample t-test. Receiver operating characteristic curves were constructed to estimate the area under the curve (AUC) and to determine optimal cutpoints.  Results: Ninety-seven women were studied; 85 were enrolled preoperatively and 12 postoperatively after a diagnosis of BLE. Median length of follow-up overall was 8 months. Of the 97 women, 46 had BLE at one or more follow-up visit with median time to first diagnosis of 3 months. Mean measured skin thickness was 2.3 ± 0.5mm in unaffected breasts and 3.2 ± 1.0 mm in operated breasts. Women with BLE had significantly greater skin thickness in the operated breast compared to the contralateral breast, with a mean skin thickness ratio of 1.83 ± 0.57 in patients with BLE compared to 1.18 ± 0.40 among those without BLE (p<0.0001). Skin thickness ratio provided excellent discrimination for BLE, with an area under the curve (AUC) of 0.86. At a ratio of 1.32 or greater (32% greater skin thickness in operated versus contralateral breast), sensitivity and specificity for diagnosing BLE were 81% and 82% respectively. A single measure of skin thickness in the operated breast also correlated well with diagnosis of BLE, with skin thickness of 3.2 mm or greater demonstrating sensitivity of 78% and specificity of 82%, AUC 0.82.  Conclusions: Breast lymphedema results in skin edema and increased skin thickness that can be quantified with ultrasound. Measuring breast skin thickness- either as a single reading or as a ratio to the unaffected breast- may be useful in the diagnosis of breast lymphedema.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3103.
Analysis of factors associated with increased psychological distress in new outpatients at the breast clinic.
Authors: Ando N , Iwamitsu Y , Kuranami M , Okazaki S , Wada M , Yamamoto K , Watanabe M , Miyaoka H
Published: December 2010

Abstract #3110

Objective: To determine how psychological characteristics, subjective symptoms, and a family history of breast cancer affect the mood states of outpatients with mammary gland complains at the first hospital visit.  Participants and methods: Written consent to participate in the study was provided by 242 outpatients with mammary gland complains at Kitasato University hospital from November 2004 to January 2007. Participants either visited our hospital directly, or were referred here from another clinic. Participants were asked to complete questionnaires determining scales of the following: trait anxiety (State-Trait Anxiety Inventry-Trait; STAI-Trait), negative emotion suppression (Courtauld Emotional Control Scale; CECS), life stress events (Life Experiences Survey; LES), and mood states (Profile of Mood States; POMS) and return them either by mail or at the time of the next clinical examination. In addition, we examined subjective symptoms (lump, pain, abnormal nipple discharge, or deformed nipple) and family history of breast cancer based on answers to the interview sheet filled out by patients on their first visit to the hospital. We excluded 45 patients who submitted incomplete answers, 38 who did not reply, and 5 who were considered to be ineligible for other reasons. The analysis covered a total of 154 patients (age (years); mean=49.94, SD=12.22). Approval for this study was granted by the Institutional Review Board of Kitasato University School of Medicine and Hospital.  Results and conclusion: We performed multiple regression analysis (forced entry method) to assess how mood states (POMS score) are affected by the following factors: age at the time of first visit, trait anxiety (STAI-Trait score), emotional suppression (CECS score), number of life stress events (LES total score), number of negative evaluations of life stress events (LES balance score), subjective symptoms, and a family history of breast cancer. We obtained a significant model (adjusted R2=0.558, p<0.01) in which trait anxiety, emotional suppression, number of life stress events, and the standard partial regression coefficient of subjective symptoms were found to be statistically significant (beta=0.618, 0.111, 0.181, 0.118; p<0.05, respectively). This suggests that mood states at the first visit are less positive when patients have high trait anxiety, emotional suppression, many life stress events, and subjective symptoms. In particular, trait anxiety had a particularly large impact on mood states, indicating the importance of psychological assistance.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3110.
European and North American scientific meetings under review: presentation and subsequent publication of breast cancer related abstracts in peer-reviewed journals.
Authors: Costa SD , Ignatov AS , Bischoff J , Taran AF
Published: December 2010

Abstract #3115

Introduction: The number of scientific meetings with breast cancer-related topics increases constantly and therefore so does the number of presented abstracts. Many of these abstracts are not reported in peer-reviewed journals post-conference. This lack of final publication constitutes a loophole in scientific reporting. Furthermore, it retrospectively assesses the quality of the review process the abstracts undergo prior to the meetings. We critically reviewed the publication rates of breast cancer-related abstracts submitted to the four major oncology meetings for breast cancer in Europe and North America in 2002.  Material and methods: The authors identified all breast cancer-related abstracts presented or published at the annual meetings of the ASCO, SABCS, EBCC and ESMO in 2002. First, a MEDLINE search identified the abstracts written by the first, second and last authors that matched a journal article by these authors. Second, the match between the study described in the abstract and full publication was determined.  Results: A total number of 1620 abstracts were analyzed.  Mean rate of full publication: 44,5%; publication rate of EUR meetings: 33,3%; publication rate of NA meetings: 52,7% (p<0,001). Median time to full publication: 11,55 months (CI 95%;7,58 to 15,66 months; full publication for the EUR meetings: 8,59 months; full publication for the NA meetings: 13,44 months (p<0,001). Median impact factor publishing journals: 1,95 IP (CI 95% 0,9 to 2,77 IP), published abstracts of the EUR meetings: 1,09; published abstracts of the NA meetings: 2,5(p<0,001). Estimated probability for an abstract not to be published after 60 months: 55,5%; abstract of the EUR meetings: 67,5%; abstract of the NA meetings: 47,8%(p<0,001) (Figure).  Discussion: We found that only about half of all studies first presented as abstracts at major meetings were published as full papers later. Thus, those who rely on scientific evidence to make health care decisions are faced with a biased subset of scientific evidence. It is clear that full-paper reviewing in peer-reviewed journals is more complex and increases the scientific value of a paper in comparison to a meeting abstract. In the past few years the number of scientific meetings on breast cancer and the number of participants attending those has increased dramatically. Our study demonstrated that this does not imply for the quality of the presented data. We propose that scientists who publish their work in peer-reviewed journals should avoid citation of abstracts and/or talks presented even at major international meetings because they risk to rely on data that has not between reviewed thoroughly enough.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3115.
Randomized phase III study of trastuzumab monotherapy followed by docetaxel and trastuzumab versus the combination of trastuzumab and docetaxel as first-line treatment in patients with HER2 positive metastatic breast cancer.
Authors: Najagami K , Inoue K , Mizutani M , Hozumi Y , Fujiwara Y , Masuda N , Tsukamoto F , Saito M , Ohashi Y , Sano M , Noguchi S
Published: December 2010

Abstract #3132

Introduction: Treatment with trastuzumab (H) is a standard therapy for the patients with HER2 positive metastatic breast cancer (MBC) and both the combination with H and chemotherapy (CT) and H alone are very popular. However, it is unknown which is better; sequential H alone followed by combination of CT and H at disease progression or the combination with H and CT as first-line therapy. Therefore, we conducted phase III randomized trial compared them in HER2 positive MBC.  Methods: Eligible patients were HER2 positive MBC patients (pts) with measurable tumour based on RECIST, ECOG Performance status 0 or 1 and left ventricular ejection fraction (LVEF) >50%. Patients with prior CT for MBC, adjuvant H, and Docetaxel (DTX) were excluded. They were randomly assigned to sequential weekly H 2 mg/kg (loading 4 mg/kg) alone followed by combination of DTX (60 mg/m2, q3wks) and H at disease progression (arm A) or concurrent combination of H and DTX (arm B). Primary endpoints were time to progression (TTP) of H alone (arm A) and combination of H and DTX (arm B) and overall survival (OS). Secondary endpoints were overall response rate (ORR), TTP and safety in arm A and B.  Results:Of the 108 pts registered, 105 pts were eligible. Baseline characteristics of all pts in two groups were well-balanced. Median age was 57/55 years, prior adjuvant CT 38/45% and single metastatic site 30/31% in arm A and B, respectively. Median TTP in arm A was 137 days compared to 445 days in arm B (hazard ratio=4.15; P<0.0001). ORRs were 15% and 71% in arm A and B, respectively. Median OS has not been reached yet, however, the number of deaths were 11 pts in arm A and 4 pts in arm B (hazard ratio=3.36; P=0.028). Adverse event incidence of grade 3 or 4 was 51/85% in each arm. An Efficacy and Safety Evaluation Committee recommended stopping this trial based on the results of TTP and OS.  Discussion: These results suggested that the combination of H and CT is superior to sequential H alone followed by DTX and H as first-line therapy in HER2 positive MBC pts despite the number of pts did not reach to the planned sample size. We will continue further investigation based on extended follow-up period. The updated data will be presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3132.
Final results from a phase II evaluation of lapatinib (L) and bevacizumab (B) in HER2-overexpressing metastatic breast cancer (MBC).
Authors: Dickler M , Franco S , Stopeck A , Ma W , Nulsen B , Lyandres J , Melisko M , Lahiri S , Arbushites M , Koehler M , Rugo HS
Published: December 2010

Abstract #3133

Background:  HER2 overexpression has been shown to upregulate VEGF expression in pre-clinical breast cancer models. Overexpression of both HER2 and VEGF has been associated with worse clinical outcome than overexpression of either receptor alone. In pre-clinical models, combination anti-HER2 and anti-VEGF therapy has been shown to be more effective than either treatment alone. B plus trastuzumab (T) has shown promising activity in patients (pts) with HER2+ MBC, however the cardiac toxicity of this regimen requires further study. L, an oral dual tyrosine kinase inhibitor of EGFR and HER2, is approved in combination with capecitabine after T-based therapy for HER2+ MBC. L may have less cardiac toxicity and may be a safer and more effective alternative to T. This hypothesis was evaluated in a phase 2 trial of L+B in HER2+ MBC pts.  Methods:   This single-arm study was designed to evaluate L (1500 mg PO daily) plus B (10 mg/kg IV q2wk) in 50 HER2+ MBC patients. The primary endpoint is crude progression-free survival (PFS) rate at 12 weeks with 84% power to detect a clinically significant PFS rate of 60%; secondary endpoints include toxicity and response per RECIST. Efficacy was assessed at Week 6, 12, and q12wks thereafter. HER2-overexpression was defined as local FISH-positive or IHC 3+ results. Serial evaluation of circulating tumor and endothelial cells and HER2 extracellular domain was performed.  Results:  Enrollment to this study ended in March 2008 (n=52). Data are presently available on 32 of 52 pts enrolled before January 1, 2008. Pts received a median of 5 prior MBC therapies (range 0-15); 88% received prior T (median 19.7 months; range 1.2-56.8 months). The most frequently reported AEs included diarrhea (81%), rash (66%), nausea (56%), fatigue (56%), and emesis (46%). Four asymptomatic LVEF declines were reported (three grade 2 events; one grade 1 event), as were nine cases of hypertension (eight grade 1 or 2 events; one grade 3 event) and one grade 3 GI hemorrhage. 27/32 patients were evaluable for response; five withdrew prior to first radiologic assessment (two due to toxicity, three due to investigator/pt request). The crude 12-week PFS rate was 63% (20/32 did not progress by Week 12); overall response rate (complete/partial response) was 13%, and the clinical benefit rate (complete/partial response or stable disease for ≥ 24 weeks) was 34%.  Conclusions:L+ B is well tolerated and has shown promising activity in heavily pretreated HER2+ MBC pts. Final efficacy and safety data will be presented on the full study cohort.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3133.
Circulating regulatory (CD4+CD25+FOXP3+) T cells decrease in breast cancer patients after vaccination with an Ii-Key-modified class II HER2/neu peptide (AE37).
Authors: Gates JD , Benavides LC , Carmichael MG , Hueman MT , Holmes JP , Khoo S , Stojadinovic A , von Hofe E , Ponniah S , Peoples GE
Published: December 2010

Abstract #3134

Background: CD4+CD25+FOXP3+ regulatory T cells (Tregs) have been implicated in the suppression of immune responses against various tumors. To monitor the potential induction of Tregs in breast cancer (BrCa) patients receiving a modified HLA Class II HER2/neu peptide (AE37) vaccine in a clinical trial, we have analyzed peripheral blood lymphocytes (PBL) from vaccinated patients for the presence of Tregs and correlated our findings with ex vivo immune assays and in vivo delayed type hypersensitivity (DTH) responses to the vaccine. Methods: Fifteen BrCa patients have completed 6 monthly injections of the AE37+GM-CSF vaccine in a dose escalation safety study. The AE37 peptide consists of a HER2/neu peptide (776-790) linked to the Ii-Key moiety of the HLA Class II-associated invariant chain, which enhances epitope interaction with the Class II molecule. PBL obtained pre- and post-vaccination were stained with anti-CD4/CD25 (n=15) and FOXP3 (n=9) antibodies (PCH101 and 236A/E7) and analyzed by flow cytometry. Cells were also stimulated ex vivo with AE37 peptide to measure IFN-γ ELISPOT, proliferation (3H-thymidine-cpm) and cytokine secretion (TGF-β). DTH responses to the AE37 peptide pre- and post-vaccination were also recorded. Results: The mean CD4+ and CD4+CD25+ T cell populations for all patients (n=15) did not change from pre- to post-vaccination (CD4+ = 52.3+3.3% vs. 50.5+3.9%, p=0.6; CD4+CD25+ = 1.9+0.2% vs. 2.4+0.5%, p=0.2). Tregs (CD4+CD25+FOXP3+) were reduced in all 9 patients tested pre- to post-vaccination for both FOXP3 antibodies (Ab) (FOXP3 Ab1 = 2.1+0.2% vs. 1.1+0.1%, p=0.002; FOXP3 Ab2 = 2.0+0.2% vs. 1.0+0.2%, p=0.0009). There was no difference in pre- to post-vaccination levels of TGF-β (2720+582 pg/ml vs. 3387+848 pg/ml; p=0.9). AE37-specific proliferative responses increased from pre- to post-vaccination (34+23cpm vs. 6427+1431 cpm; p<0.001). ELISPOT demonstrated an increased response from pre- to long term (6-12mo.) post-vaccination (Median – 2 vs. 34 spots/106 cells; p=0.003). DTH responses increased in all patients from pre- to post-vaccination (3.6+1.4 mm vs. 56.0+9.4 mm; p<0.0001), and there appeared to be an inverse relationship between the degree of Treg reduction and the size of DTH response to AE37 (R2=0.83).  Discussion: The novel AE37 HER2/neu peptide vaccine does not result in increased levels of Tregs. Furthermore, the reduced levels of Tregs in vaccinated patients appear to be associated with more robust responses in ex vivo immune assays and in vivo DTH reactions suggesting that the AE37 vaccine may be clinically useful.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3134.
A phase I study of weekly dosing of trastuzumab-DM1 (T-DM1) in patients with advanced HER2+ breast cancer.
Authors: Krop IE , Mita M , Burris HA , Birkner M , Girish S , Tibbitts J , Holden SN , Lutzker SG , Modi S
Published: December 2010

Abstract #3136

Background: T-DM1, a novel HER2 antibody-drug conjugate (ADC) in development for HER2+ breast cancer (BC), combines activity of trastuzumab (T) with the targeted delivery of maytansinoid DM1 (potent antimicrotubule agent) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20-100x more potently than vincristine. It is bound to T by MCC, a linker that is stable with protease activity and under many pH or redox conditions. T-DM1 is the first ADC with an MCC linker to enter clinical trials. Main preclinical AEs were reversible transaminase (TA) elevations, reversible platelet decreases, and neuropathy. A phase I study of T-DM1 every 3 wks (q3w) in patients (pts) with advanced HER2+ BC who progressed on T-containing chemotherapy regimen, the maximum tolerated dose (MTD) was 3.6 mg/kg, with DLT of grade (Gr) 4 thrombocytopenia (TCP); tumor responses were seen in 5 of 9 pts (4 confirmed, 44%) with measurable disease treated at MTD. We undertook this dose escalation study of T-DM1 given once/wk (q1w) to explore pharmacokinetics (PK), safety, and tolerability of more frequent dosing.  Methods: Pts with advanced HER2+ BC who had progressed on a T-containing chemotherapy regimen received T-DM1 IV q1w continuously. Dose levels were escalated in successive 3+3 cohorts if DLT was seen in <1/3 of pts within 21 days of Cycle 1 Day 1.  Results: As of 19 May 2008, enrollment is complete with 27 pts (15 at the MTD). Data is available for 19 pts [median age 54.0 (range 41-71); all PS 0-1; median number prior metastatic chemo agents 5.0 (range 2-8); median wks of prior trastuzumab 122 (range 29-325)] who have received 246 doses of T-DM1 at 1.2, 1.6, 2.0, 2.4, and 2.9 mg/kg. Common related AEs include fatigue (Gr1, 3 pts; Gr2, 4 pts; Gr3, 1 pt), thrombocytopenia (Gr 1, 4 pts; Gr2, 3 pts; Gr3, 2 pts), nausea (Gr1, 7 pts; Gr 2, 1 pt), TA elevations (Gr1, 1 pt; Gr2, 4 pts; Gr3, 1 pt), vomiting (Gr1, 3 pts; Gr2, 1 pt) and headache (Gr1, 2 pts; Gr2, 1 pt). Dose-limiting toxicity was seen in 2 pts at 2.9 mg/kg (toxicity preventing retreatment on Cycle 1 Day 8, from Gr2-3 thrombocytopenia). No Gr4 AEs or cardiac toxicity were seen. Preliminary PK analyses suggest that steady-state T-DM1 exposure at 2.4 mg/kg q1w will be ∼2x that associated with 3.6 mg/kg q3w. Of 15 pts evaluable for response, 9 had partial responses (8 confirmed, 53%).  Conclusions: The MTD of T-DM1 on a weekly schedule is 2.4 mg/kg. Related Gr ≥2 AEs were reversible and manageable. The activity and safety results observed on q1w dosing were consistent with q3w dosing, supporting further study. Three Phase II trials of q3w T-DM1 in advanced HER2+ BC will enroll pts in 2008; preliminary results from the first trial will be reported in 2008.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3136.
Optimal method of dosing HER2/neu peptide vaccines: U.S. Military Cancer Institute Clinical Trials Group Study 1-01, 1-02, 1-03, and 1-04.
Authors: Benavides LC , Gates JD , Holmes JP , Mittendorf EA , Ponniah S , Peoples GE
Published: December 2010

Abstract #3139

Background: Our Cancer Vaccine Development Program has performed phase I and II clinical trials using immunogenic peptides from the HER2/neu protein. AE37 (aa:776-790+Ii-Key) is HLA promiscuous whereas E75 (aa:369-377) and GP2 (aa:654-662) are HLA-A2/A3+ restricted. The peptides are located on the intracellular, extracellular, and transmembrane portions of the HER2/neu protein. We evaluate patients who required dose reductions and compare them to those who did not in our three peptide vaccine trials to determine the immunologic and clinical relevance of different responses to the peptide vaccines. Methods: Three vaccine trials were performed separately with similar dose escalation design by varying the amount of AE37, GP2 or E75 peptide and GM-CSF adjuvant. Dose reductions (DR) were made in event of significant toxicity (>100mm local or ≥grade 2 systemic) by decreasing GM-CSF (or peptide if no GM-CSF) by 50% for subsequent inoculations. We compared patients necessitating DR and those who did not. Immune response was measured ex vivo via 3H-thymidine proliferative assays or HLA-A2:Ig dimer assays and in vivo via DTH reactions pre- and post-vaccine. Recurrence and mortality data were available for E75 treated patients at 30-month median follow-up. Results: 132 patients underwent peptide vaccination and 39 patients required DR (Table 1).    No patient had grade 3-5 local or systemic toxicities. DR patients, particularly those reduced for robust local reactions (DR-L), had greater immune responses ex vivo and in vivo. The post-vaccine DTH in DR-L patients compared to all other vaccinated patients was significantly larger in E75 (24.5±4.1mm vs. 12.7±1.3mm; p=0.001) and trended towards significant in AE37 (69.4±10.3mm vs. 35.8±14.9mm; p=0.08) and GP2 (48.9±14.1mm vs. 24.1±3.3mm; p=0.08). No recurrences or deaths were noted in the E75 DR patients; but for patients not requiring dose reductions there were 10 (12.5%) recurrences and 1 (1.25%) death.Discussion: All three peptide vaccines are safe and well-tolerated with minimal toxicity. The safety was partly due to reducing GM-CSF (or peptide if no GM-CSF) by 50% for patients with >100mm local reactions or >grade 2 systemic toxicity. DR patients, particularly DR-L patients, immunological responses were larger. This increased immune response (noted by DTH) suggests improved clinical response as there have been no recurrences or deaths among DR patients. Our analysis indicates that the optimal method of dosing HER2/neu peptide vaccines consists of constant peptide dose with a large enough dose of adjuvant to generate robust local reactions and that when local reactions are >100mm performing DR of adjuvant by 50% for subsequent inoculations.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3139.
Correlation of tumor burden, liver and bone metastasis with serum extracellular domain HER2 expression in front-line metastatic breast cancer.
Authors: Johnston S , O'Rourke L , Wang W , Pegram M , Press MF , Maltzman J
Published: December 2010

Abstract #3146

Background: Although serum extracellular domain (sECD) HER2 levels can be easily measured by enzyme immunoassays, the potential clinical utility of HER2 extracellular domain protein shed in the serum is not established. High serum protein levels may be indicative of metastatic disease to the liver or perhaps greater tumor burden. EGF30008 is a double-blind, placebo-controlled phase III trial evaluating the effect of letrozole with/without lapatinib in previously untreated postmenopausal women with hormone receptor-positive metastatic breast cancer. Levels of sECD HER2 were collected on all 1,286 women at baseline and every 4 weeks on study including at disease progression.  Methods: Baseline serum levels and tumor characteristics were collated in blinded fashion for all 1,286 patients in the trial (data cut off 12May08). Patients with baseline serum protein levels ≥ 15 ng/mL were defined as sECD HER2+. Correlations were assessed between baseline serum protein levels and baseline liver disease and bone-only disease and total tumor burden (as defined by number of metastatic sites). Chi-square test was applied to assess the correlation between serum protein levels and liver disease or bone-only disease. Wilcoxon rank-sum test using normal approximation was used to compare total tumor burden and baseline protein levels.  Results: Among sECD HER2+ patients, 42% had at least one liver metastasis, whereas 20% of sECD HER2-negative patients had at least one liver metastasis (P < 0.0001). No correlation exists between baseline serum protein level and bone-only disease (P = 0.64). Patients who were sECD HER2+ had a greater total tumor burden (mean metastatic sites = 5.4; standard deviation = 3.2; median = 5) compared with patients who were sECD HER2-negative (mean metastatic sites = 4.4; standard deviation = 3.1; and median = 4; P < 0.0001).  Conclusion: High baseline sECD HER2 strongly correlates with tumor burden. There was also a significant correlation between sECD and liver metastases, but no correlation at all with bone-only disease. These analyses will be repeated after the database is finalized and unblinded. Our analysis is limited to detection of the number of metastatic sites and is not sensitive to the individual sizes of metastases. In addition, another potential explanation for the low sensitivity of HER2 detection by sECD is that small metastatic deposits that are HER2+ in situ do not shed enough sECD into the serum to be detected by the assay. Conversely, some very large HER2-negative tumors do in fact shed measurable sECD if the tumor bulk is very high, even though in situ they may be nonamplified. A future analysis will take the sum of the longest diameters of all known lesions and compare it to sECD HER2 levels.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3146.