bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PD04-06: Molecular Phenotypes of DCIS predict Invasive and DCIS recurrence
Authors: Williams KE , Barnes NLP , Cheema K , Dimopoulos N , Bundred NJ , Landberg G 
Published: August 2014

Abstract
Introduction: Molecular phenotypes of invasive breast cancer predict early recurrence and survival. DCIS exhibits similar phenotypes but their frequency and clinical significance remain uncertain. To determine whether molecular phenotypes of DCIS predict recurrence, 273 women (median age 57 years) with primary DCIS who were screened for or entered DCIS trials (Iressa/Lapatinib/ERISAC) in one unit from 1990–2010 were studied.
Methods: HER2, oestrogen receptor (ER) and progesterone receptor (PR) expression within primary DCIS were established using immunohistochemistry within the trial protocols. HER2 was scored 0 (absent) to 3 (maximum). Scores ≥2 were taken as positive if amplified on FISH testing. ER and PR scored positive if ≥5% of cells stained. 64.2% patients were ER positive, 43.3% were HER2 positive and 31.8% were high-grade lesions. 94 underwent mastectomy whilst 185 had BCS.
Results: There was an overall recurrence rate of 20.14% after a median follow-up period of 74 months (range 12–240). Of these recurrences, 36.4% were invasive. Conservation surgery (BCS) was used in 185 women who suffered 47 recurrences. Molecular phenotype predicted local recurrence by Log Rank analysis (P &lt; 0.01) and invasive recurrences (P &lt; 0.016) overall and in the BCS group remained predictive of invasive recurrence (p &lt;0.005) and overall recurrence (p &lt; 0.001).

ER negative DCIS had higher invasive recurrence (p &lt; 0.01: Chi-squared). Grade 3 was a weak predictor of overall (p &lt; 0.02) but not invasive recurrence. HER2 positive DCIS had poorer cumulative 5-year disease-free survival than HER2 negative cases (p = &lt;0.001, Kaplan-Meier), irrespective of ER status. On multivariate COX regression analysis, HER2 positivity was an independent predictor of increased recurrence risk (p = 0.01) H.R. 7.39, 95% CI 1.61–33.8)
Discussion: Determination of molecular phenotypes of DCIS aids identification of women at high-risk of recurrence. ER-HER2+ patients need maximal adjuvant treatment to avoid invasive recurrence whereas lower-risk ER+HER2− patients might avoid adjuvant radiotherapy.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD04-06.
Abstract PD05-09: Whole-genome progression of breast cancer from early neoplasia to invasive carcinoma
Authors: West RB , Kashef-Haghighi D , Newburger D , Weng Z , Brunner A , Salari R , Guo X , Troxell M , Zhu S , Varma S , Sidow A , Batzoglou S 
Published: August 2014

Abstract
Cancer evolution involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Early breast neoplasias include usual ductal hyperplasia, columnar cell lesions, and flat epithelial atypia and some are thought to represent precursor stages. To elucidate their role in cancer evolution we performed comparative whole genome sequencing of early neoplasias, matched normal tissue, and carcinomas from six patients. The identified somatic mutations served as lineage markers to build trees that relate the tissue samples. On the basis of the lineage trees we inferred the order, timing, and rates of mutational events. We find that in a subset of cases, the last common ancestor of an early neoplasm and a carcinoma was hypermutated and had several aneuploidies, and that evolution further accelerated in the carcinoma lineage. In contrast to highly advanced tumors that are the focus of much of current cancer genome sequencing, the early neoplasia genomes, and the carcinomas as well, harbor a striking paucity of potentially functional somatic point mutations. The earliest significant events we could detect, those changes that occurred in common ancestors of neoplastic and tumor cells, are aneuploidies. Several aneuploidies are recurrent, suggesting that they are among the earliest genomic events that predispose breast tissue to eventual development of invasive carcinoma.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD05-09.
Abstract PD07-06: NEO-ZOTAC: Toxicity data of a phase III randomized trial with NEOadjuvant chemotherapy (TAC) with or without ZOledronic acid (ZA) for patients with HER2-negative large resectable or locally advanced breast cancer (BC)
Authors: van de Ven S , Liefers G-j , Putter H , van Warmerdam LJ , Kessels LW , Dercksen W , Pepels MJ , Maartense E , van Laarhoven HWM , Vriens B , Smit VTHBM , Wasser MNJM , Meershoek-Klein Kranenbarg EM , van Leeuwen-Stok E , van de Velde CJH , Nortier JWR , Kroep JR 
Published: August 2014

Abstract
Background: The role of bisphosphonates (BP) when added to the (neo)adjuvant treatment of BC in enhancing the efficacy of therapy is still unknown. NEOZOTAC investigates the efficacy of ZA added to neoadjuvant chemotherapy in patients with HER2-negative BC.
Trial design: NEOZOTAC is a Dutch multicenter study. Patients are 1:1 randomized to 3-weekly TAC (docetaxel 75mg/m2, adriamycin 50 mg/m2 and cyclophosphamide 500 mg/m2 i.v., day 1) chemotherapy supported by pegfilgrastim (6 mg sc), day 2 with or without ZA (4 mg i.v. within 24 hr after chemotherapy) q3 weeks.
Eligibility criteria: Main inclusion criteria: stage II or III, measurable, HER2-negative BC, age ≥18 years, WHO 0–2, adequate bone marrow-, renal-, and liver function, absence of prior BP usage and absence of active dental problems.
Study endpoint: The primary endpoint is the pathologic complete response (pCR) rate. Secondary endpoints are toxicity, clinical response, tumor heterogeneity in core biopsy vs. operation specimen, and (disease free) survival. Optional side studies include fluorescent imaging (SoftScan®), changes in bone markers, single nucleotide polymorphisms and the insulin-like growth factor pathway, circulating tumor and endothelial cells and the false-negative rate of the sentinel node biopsy after neoadjuvant chemotherapy.
Statistical Methods: Using a 5% significance level based on the two-sided Fishers exact test with a power of 80%, 250 patients (125/arm) are needed to show an improvement of the pCR-rate from 17% to 34% in the experimental arm. Randomization was done according to the Pococks minimisation technique stratified by cT, cN, and estrogen receptor status. Toxicity is analyzed using the Exact (2-sided) Chi-Square test.
Results: From July 2010 to April 2012, 250 patients from 25 participating sites were randomized. Toxicity data of 173 patients are currently available and data of all 250 patients will be presented at SABCS. Patient characteristics are presented in table 1.

Hematological and non-hematological toxicities were not significantly different between both treatment arms. Main grade 3/4 NCI-CTCv4 toxicities were neutropenia (8%), followed by febrile neutropenia (7%), fatigue (6%), diarrhea, hypertension, nausea (3%) and vomiting (1.2%). Bone pain, myalgia, and hypocalcemia occurred in one patient in the TAC-ZA arm (0.6%). Osteonecrosis of the jaw was not observed.
Conclusions: Neoadjuvant TAC supported by pegfilgrastim plus ZA is feasible. No significant difference in toxicity are reported compared with the control arm.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-06.
Abstract PD10-05: HLA-DQA1*02:01/DRB1*07:01 as a biomarker for lapatinib-induced hepatotoxicity: prospective confirmation in a large randomised clinical trial (TEACH, EGF105485)
Authors: Spraggs CF , Schaid DJ , Parham LR , McDonnell SK , Briley LP , King KS , Rappold E , Goss PE 
Published: August 2014

Abstract
Hepatotoxicity is associated with small molecule tyrosine kinase inhibitors (TKI) in use for the treatment of a variety of cancers. Retrospective studies have identified and confirmed that specific Class II Human Leukocyte Antigen (HLA) alleles are strongly associated with ALT elevation in women treated with the TKI lapatinib for breast cancer. This study aimed to further evaluate and validate the role of the specified HLA alleles as predictors of elevated ALT in a pre-defined analysis of a large, randomized, double-blind, placebo-controlled study of lapatinib monotherapy in early stage HER2 positive breast cancer, the TEACH study (Tykerb Evaluation After Chemotherapy, EGF105485).
This prospectively defined pharmacogenetic study compared the frequency of hepatobiliary adverse events between pre-specified Major Histocompatibility Complex (MHC) genetic variants, including the HLA alleles DQA1*02:01 and DRB1*07:01. The primary focus was on elevated ALT, as well as rare cases of concurrent ALT (&gt;3x ULN) and bilirubin (&gt;2x ULN) elevation, which represent possible Hy's Law cases and a high risk of acute liver failure, among 1194 patients randomized to lapatinib treatment from whom pharmacogenetic data was available.
This study prospectively validated prior reports of the association of the specified MHC variants with elevated ALT among women treated with lapatinib. The strongest effects were observed for carriers of the HLA alleles DQA1*02:01 and DRB1*07:01, with odds ratios of 20 (95% CI: 8–40) between cases (n = 34) and controls (n = 807–808). These two HLA alleles are highly correlated, inherited together in most individuals and are consistent with a single genetic association. The overall risk of patients having an ALT (&gt;3xULN) elevation was 3.0% and 0.7% during treatment with lapatinib and placebo respectively. Carriers of either HLA allele had a 12% chance (positive predictive value) of having an elevated ALT (&gt;3xULN), in contrast to a 0.9% risk (negative predictive value, 99.1%) for non-carriers of the specified HLA alleles. These associations were maintained for higher ALT elevation thresholds and for cases of concurrent ALT and TBL elevation, consistent with possible Hy's Law cases. These results strongly support the role of Class II HLA-modulated immune mechanisms in lapatinib-induced hepatotoxicity.
Our results validate the large strength of association of the HLA alleles DRB1*07:01 and DQA1*02:01 with hepatotoxicity and provide the possibility of managing the risk of hepatotoxicity in women receiving lapatinib for early or late stage HER2 positive breast cancer. This association with immune mechanisms may have implications for toxicities with other TKIs in current use in cancer patients.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-05.
Abstract PL-1: Hormones and the Breast: Local and Environmental Interactions
Authors: Brisken C , Rajaram R , Ayyannan A , Beleut M , Yalcin O 
Published: August 2014

Abstract
A woman's reproductive history affects her risk to get breast cancer. In particular, the number of menstrual cycles she experiences correlates with risk. We use tissue recombination experiments and different mouse mutant models to discern the roles of the ovarian hormones estrogens and progesterone act in the mammary gland. While estrogens drive pubertal development, progesterone is the major driver of proliferation in the adult mammary epithelium. Both steroids rely strongly on paracrine signaling to elicit cell proliferation and other biological effects.
Perinatal exposure to environmentally relevant concentrations of a high production volume chemical, bisphenol A, that is detected in human due to exposure through consumer products, results in persistent changes in the mammary gland. The cell number is increased in in adult females as is the response to progesterone.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PL-1.
Abstract S1-2: ATLAS – 10 v 5 years of adjuvant tamoxifen (TAM) in ER+ disease: Effects on outcome in the first and in the second decade after diagnosis
Authors: Davies C , Pan H , Godwin J , Gray R , Peto R ,   ATLAS Collaborators Worldwide
Published: August 2014

Abstract
Background: In ER+ early breast cancer, 5 years of tamoxifen greatly reduces recurrence throughout the first decade (years 0–9) with little further gain later, and reduces breast cancer mortality (BCM) substantially throughout years 0–14 (EBCTCG, Lancet 2011; 378: 771–84 – see Table). It is not known how 10 years TAM compares with the current standard of just 5 years TAM.
Methods: In 1996–2005 the international ATLAS trial randomized 6846 women with ER+ disease who had had ∼5 years of adjuvant TAM to continue another 5 years (to year 10) or stop at year 5 (control). Annual follow-ups recorded compliance, hospital admissions, breast cancer recurrence (including new contralateral), any other new primary cancer and cause of death.
Results: Compliance was ∼80%, as after 2 years 84% of those allocated continue and 4% of those allocated stop were still taking endocrine treatment (&gt;99% TAM). With mean 7.1 woman-years follow-up (30,000 w-y in years 5–9, 16,000 in years 10–14, 2000 later), 1328 recurrences were reported (900 in years 5–9, 379 in years 10–14). Recurrence was significantly lower with10 than 5 years TAM (Table: logrank 2p = 0.002, rate ratio (RR)=0.90 se 0.06 in years 5–9 and 0.75 se 0.08 in years 10+). So were both BCM (2p = 0.01, RR = 0.97 se 0.10 in years 5–9 and 0.71 se 0.09 in years 10+) and all-cause mortality (2p = 0.01, with no increase in non-BCM). Proportional risk reductions were homogeneous by country, age and stage. Kaplan-Meier risks in years 5–14 (K-M) were: recurrence 21.4 vs 25.1%, BCM 12.2 vs 15.0%. Uterine cancer K-Ms in those randomized at age 50+ were: incidence 2.6 vs 1.6% (2p = 0.08), mortality 0.2 vs 0.2%. In pre-menopausal women (where AIs are not an alternative to TAM) there was no apparent excess of uterine cancer.
Discussion: Compared with just 5 years TAM, continuing TAM to year 10 safely protects further against recurrence and, particularly during the second decade, BCM. Combining results from ATLAS and the EBCTCG meta-analyses of 5 years TAM vs none (both had ∼80% compliance), in a hypothetical trial of 10 vs 0 years TAM with ∼80% compliance, 15-year BCM would be reduced by at least one-third. Hence, full compliance with 10 years TAM would yield even greater benefit (Table). Further follow-up of ATLAS will assess more reliably the apparently substantial mortality reduction in the second decade after diagnosis.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-2.
Abstract S1-6: Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2− advanced breast cancer (BC)
Authors: Finn RS , Crown JP , Lang I , Boer K , Bondarenko IM , Kulyk SO , Ettl J , Patel R , Pinter T , Schmidt M , Shparyk Y , Thummala AR , Voytko NL , Breazna A , Kim ST , Randolph S , Slamon DJ 
Published: August 2014

Abstract
Background: PD 0332991, a selective inhibitor of CDK 4/6, prevents cellular DNA synthesis by blocking cell cycle progression. Preclinical studies in a BC cell line panel identified the luminal ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to PD 0332991 (Finn et al. 2009). Synergistic activity was also observed in vitro when combined with tamoxifen. After determination of the recommended phase 2 dose in combination with letrozole (letrozole 2.5 mg QD plus PD 0332991 125 mg QD on Schedule 3/1), a randomized phase 2 study comparing letrozole alone (L) to letrozole plus PD 0332991 (L+P) was initiated.
Methods: The phase 2 portion of the study was designed as a two-part study; Part 1 enrolled post- menopausal women with ER+/HER2− advanced BC; Part 2 in addition to ER+/HER2− as eligibility criteria, screened for CCND1 amplification and/or loss of p16 by FISH. The primary endpoint is progression-free survival (PFS); secondary endpoints include response rate, overall survival, safety, and correlative biomarker studies. In both parts, post-menopausal women with ER+/HER2− advanced BC were randomized 1:1 to receive letrozole either with or without PD 0332991. Pts continue on assigned study treatment until disease progression, unacceptable toxicity, or consent withdrawal, and are followed for tumor assessments every 2 months.
Results: 66 pts were randomized in Part 1 and 99 pts in Part 2. Preliminary results from Part 1 of this study have been previously reported (IMPAKT Breast Cancer Conference, Abstract #292, Finn et al. May 2012) demonstrating a significant improvement in median PFS in the L+P vs. L arm (HR = 0.35; 95% CI, 0.17 to 0.72; p = 0.006). With the additional 99 pts randomized in Part 2 (N = 165), the statistically significant improvement in median PFS (26.2 vs. 7.5 months, respectively) continues to be observed with a HR=0.32 (95% CI, 0.19 to 0.56) with p &lt;0.001. The response rate for the L+P arm (n = 84) was 31% vs. 26% for the L arm (n = 81) and the clinical benefit rate was 68% vs. 44%, respectively. The most commonly reported treatment-related AEs in the combination arm were neutropenia, leukopenia, anemia, and fatigue. The updated results from the combined Part 1 and Part 2 group will be presented in December 2012.
Conclusions: The combination of PD 0332991 and letrozole is well tolerated and shows encouraging clinical benefit, confirming the sensitivity of ER+ BC to PD 0332991 observed in preclinical models. A phase 3 trial in this setting will commence in 2013.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-6.
Abstract S3-2: Chemotherapy prolongs survival for isolated local or regional recurrence of breast cancer: The CALOR trial (Chemotherapy as Adjuvant for Locally Recurrent breast cancer; IBCSG 27-02, NSABP B-37, BIG 1-02)
Authors: Aebi S , Gelber S , Láng I , Anderson SJ , Robidoux A , Martín M , Nortier JWR , Mamounas EP , Geyer CE , Maibach R , Gelber RD , Wolmark N , Wapnir I 
Published: August 2014

Abstract
Introduction Patients with isolated local and regional recurrences (ILRR) of breast cancer (BC) have a high risk of developing distant metastasis and dying from BC. We investigated the impact of chemotherapy (C) on disease-free survival (DFS) and overall survival (OS) after ILRR.
Methods Patients with resected ILRR were stratified according to prior chemotherapy (yes vs. no), ER and/or PgR status of the recurrent tumor (both negative vs. either positive), and location of recurrence (breast vs. scar/chest wall vs. lymph nodes). Radiation, hormone and HER2 directed therapies were delineated in the protocol. Participants were randomly assigned to receive C or none. Multidrug C for at least 4 courses was recommended. Drug selection was at the discretion of the investigator. Slow accrual led to premature closure of the trial before achieving the planned sample size of 265.
Results The trial accrued 162 patients (C, 85; control, 77) from 2002–2010. The groups were balanced in regard to the characteristics listed in the table below.

At a median follow up of 4.9 years, there were 24 (28%) DFS events and 9 (11%) deaths in the C group compared with 34 (44%) DFS events and 21 (27%) deaths in the control group, corresponding to a 5-year DFS of 69% vs. 57%, [DFS HR (C/control) = 0.59, 95% CI (0.35, 0.99)], p =0.046] and a 5-year OS of 88% vs. 76%, [OS HR (C/control) = 0.41, 95% CI (0.19, 0.89)], p =0.02]. The results remained significant for both DFS and OS in multivariable Cox proportional hazards modeling controlling for ILRR location, disease-free interval, ER status and prior adjuvant chemotherapy. Adjuvant C was particularly effective for women with ER-negative ILRR: 5-year DFS 67% vs. 35%, [DFS HR (C/control) = 0.32, 95% CI (0.14, 0.73)], p =0.007] and OS 79% vs. 69%, [OS HR (C/control) = 0.43, 95% CI (0.15, 1.24)], p =0.12]. Results for the ER-positive ILRR cohort were: 5-year DFS 70% vs. 69%, [DFS HR (C/control) = 0.94, 95% CI (0.47, 1.89)], p =0.87] and OS 94% vs. 80%, [OS HR (C/control) = 0.40, 95% CI (0.12, 1.28)], p =0.12].
Conclusion Adjuvant chemotherapy should be recommended for patients with completely resected isolated loco-regional recurrences of breast cancer, in particular, if the recurrence is not sensitive to endocrine therapy.
Funding NCI PHS grants U10-CA-37377, -69974, -12027, -69651, CA-75362.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-2.
Abstract S5-4: EGFR expression measured by quantitative immunofluorescense is associated with decreased benefit from trastuzumab in the adjuvant setting in the NCCTG (Alliance) N9831 trial.
Authors: Rimm D , Ballman KV , Cheng H , Vassilakopoulou M , Chen B , Gralow J , Hudis C , Davidson NE , Psyrri A , Fountzilas G , Perez EA 
Published: August 2014

Abstract
Background: Epidermal Growth Factor Receptor (EGFR, HER1) is known to heterodimerize with HER2 and may impact the effectiveness of trastuzumab. Historically, EGFR has been difficult to measure; thus there is no evidence regarding its effects on trastuzumab clinical therapy. Here we use a new, standardized, quantitative immunofluorescence assay and a novel EGFR antibody to evaluate the correlation between EGFR expression and clinical outcome in a cohort from the North Central Cancer Treatment Group (NCCTG, Alliance) N9831 trial.
Methods: Of the 3505 women in the N9831 trial, tissue microarrays were constructed that allowed analysis of 1,444 patients randomly assigned to receive chemotherapy alone (Arm A), sequential trastuzumab after chemotherapy (Arm B) or concurrent trastuzumab with chemotherapy (Arm C). Fluorescence-based, standardized measurement of EGFR was done using the rabbit monoclonal EGFR antibody D38B1 on the AQUA platform (HistoRx). EGFR expression levels were analyzed as a continuous variable and dichotomized using recursive partitioning to define an optimal cut point. The cut point was validated on an independent retrospective cohort comprised of 130 patients with HER2-positive metastatic breast cancer who received trastuzumab.
Results: EGFR assessed as a continuous variable shows an association with disease free survival (DFS) in Arm C (p = 0.002) but not in Arms A or B. Dichotomizing EGFR expression shows that high level expression is associated with worse outcome (HR = 2.2; 95% CI 1.33–3.59, p = 0.002) in arm C. Five year DFS within the low level EGFR expression group was 71%, 74% and 90% for Arms A, B and C, respectively (log-rank p-value=0.02) and within the high level EGFR expression (n = 213) group was 62%, 76% and 74% respectively (log-rank p-value 0.22). As validation, the same cut-point was used to define high EGFR expression in a retrospective metastatic breast cancer cohort. The median progression free survival difference between EGFR high group and EGFR low group was 6.1 months (p = 0.0063) and the hazard ratio of high EGFR was 1.92 (p = 0.0073).
Conclusions: High expression of EGFR by the AQUA platform appears to be associated with decreased benefit from adjuvant concurrent (not sequential) trastuzumab and shorter PFS in the metastatic setting. The biological underpinning for these observations is being considered. Since there are other treatment options for HER2-driven tumors, this marker, once validated, could help select patients for alternative or additive therapy.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-4.