bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PD08-06: Significant Clinical impact of recurrent BRCA1 and BRCA2 (BRCA) mutations in Mexico
Authors: Villarreal-Garza C , Herrera LA , Herzog J , Port D , Mohar A , Perez-Plasencia C , Clague J , Alvarez RMa , Santibanez M , Blazer KR , Weitzel JN 
Published: August 2014

Abstract
Background: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cancer cause of death in Hispanic women. Although the incidence of breast cancer in Hispanics is less than that for non-Hispanic white women, our studies on the prevalence of deleterious mutations in the BRCA genes among high-risk Hispanics in the US suggest that BRCA mutations may account for a higher proportion of BC in this population. However, a lack of research on BRCA mutations in Hispanics has limited the implementation of prevention efforts and the scope of comparative studies of genetic factors that influence BC and ovarian cancer (OC) risk within Hispanic populations – this is especially true of Mexico where there has been little access to clinical BRCA gene analyses.
Objective/Methods: We used an economic panel assay (HISPANEL) on a mass spectroscopy platform (Sequenom) to analyze DNA from 189 cancer cases (92 unselected OC; 97 BC) from the National Cancer Institute in Mexico City for recurrent BRCA mutations, including a large rearrangement (BRCA1 ex9-12del) that we hypothesize is a Mexican founder mutation.
Results: Overall, 14% (27/189) harbored a germline BRCA mutation (25 BRCA1, 2 BRCA2) detected by the HISPANEL (17% in OC; 11% in BC). BRCA1 ex9-12del was detected in 9.8% (9/92) of unselected OC cases, representing 56% of the 16 BRCA mutations. It also represented 36% (4/11) of the BRCA mutations detected in the BC cases. Mean age at onset of BC for BRCA-associated cases (n = 11) was 46 years old (range 31–63); 8/11 were triple negative BC (TNBC) – a BRCA mutation was detected in 24% (8/34) of all TNBC cases.
Conclusions: The remarkable frequency of the BRCA1 ex9-12del mutation, accounting for 56% of BRCA mutations in the OC cases and 36% of BC cases, supports our hypothesis of regional origin of this Mexican founder mutation approximately 1,474 years ago. Similar to our experience in the Mexican American population, the HISPANEL, which includes recurrent BRCA mutations found in women of Hispanic ancestry, appears to have high sensitivity and thus is likely to have clinical utility while reducing overall genotyping cost among underserved women in Mexico. Both in the US Hispanic populations and in Mexico, the prevalence of the Mexican founder mutation make it a significant public health issue, and presents an opportunity for cost effective in BC and OC prevention.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD08-06.
Abstract PD09-04: Homologous Recombination Deficiency (HRD) score predicts pathologic response following neoadjuvant platinum-based therapy in triple-negative and BRCA1/2 mutation-associated breast cancer (BC)
Authors: Telli ML , Jensen KC , Abkevich V , Hartman A-R , Vinayak S , Lanchbury J , Gutin A , Timms K , Ford JM 
Published: August 2014

Abstract
Background: BC that arises in BRCA1/2 mutation carriers is characterized by defective homologous recombination DNA repair. Given the clinical potential for DNA repair-targeted therapeutics, Myriad Genetics has developed a tumor DNA-based assay that can identify underlying defects in the homologous recombination pathway, regardless of etiology, including identification of BRCA1/2 mutation carriers with high sensitivity. This study was designed to assess ability of the HRD score to predict pathologic response to neoadjuvant platinum-based therapy in early-stage triple-negative and BRCA1/2 mutation-associated BC.
Methods: The HRD score was assessed in a cohort of 55 fresh frozen tumors from pts with clinical stage I-IIIA triple-negative and BRCA1/2 mutation-associated BC enrolled onto a single-arm, phase II study of neoadjuvant gemcitabine, carboplatin and iniparib. Following neoadjuvant therapy (4 cycles=11; 6 cycles=44), pathologic response was assessed using the residual cancer burden (RCB) index by a central pathologist. Twenty-nine tumors were obtained from responders (RCB 0/1) and 26 tumors were from non-responders (RCB 2/3). The HRD score was derived by count of the number of LOH regions (&gt;15 Mb and &lt; whole chromosome) observed in the tumor genome. Association of response to treatment and HRD score was performed by the Mann-Whitney U test.
Results: Germline BRCA1/2 mutation status was known in all pts and 13/55 tumors were from carriers of deleterious BRCA1 (n = 9), BRCA2 (n = 3) or BRCA1&2 (n = 1) mutations. Two mutation carriers had ER+/PR+(&gt;5%) BC. The mean HRD score for responders is 16.5 and no differences were noted between germline BRCA1/2 mutants vs. non-mutants. The mean HRD score for non-responders is 11.4. Among carriers of BRCA1/2 mutations, 12/13 achieved a favorable response. The one BRCA1 mutation carrier non-responder with TNBC had a low HRD score of 8. This pt was previously treated with chemotherapy twice 12 years prior for primary and locally recurrent contralateral TNBC. The p-value for association between response to treatment and HRD score by the Mann-Whitney U test is 0.004. If BRCA1/2 deficient samples are excluded, the association between response to treatment and HRD score remains significant (p = 0.02). Multivariate analysis that includes HRD score, BRCA1/2 genotype, age, stage, tumor grade, PAM50 subtype, ER/PR status, and cycles of therapy will be presented together with data from an additional 35 pts. Enrollment to the therapeutic trial is complete and final clinical results will be separately presented.
Conclusion: The HRD score is significantly correlated with pathologic response to platinum-based chemotherapy in early-stage triple-negative and BRCA1/2 mutation-associated BC.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-04.
Abstract PD09-09: The Akt inhibitor MK-2206 is an effective radio-sensitizer of p53 deficient triple negative breast cancer (TNBC) cells.
Authors: Connolly EP , Sun Y , Chao KC , Hei TK 
Published: August 2014

Abstract
Purpose: Triple negative breast cancer (TNBC) is an aggressive tumor with a higher locoregional recurrence compared to estrogen receptor (ER) positive breast cancer. Mutations in the PI3K/Akt/mTOR pathway leading to up-regulation of Akt occur with high frequency in TNBC. Hyperactive Akt is associated with increase radiation resistance, mediated through inhibition of apoptosis and up-regulation of DNA damage-induced G2 arrest. p53 plays a key role in mediating G1 cell cycle arrest following genotoxic stress such as radiation; p53-deficient cells however must rely on alternate mechanisms for cell cycle arrest in S- and G2-phases. Inhibition of Akt therefore would be expected to act in a synthetic lethal fashion to radiosensitize p53 deficient TNBC cells by decreasing their ability to arrest in G2. Given that p53 mutations occur in 44% of TNBC this may be an effective strategy for radiosensitizing TNBC.
Methods: Experiments were conducted using MDA-MB-468, MDA-MB-231 and SUM 149 cells, all well established models for p53-deficient TNBC. Cells were treated with MK-2206, a potent allosteric Akt inhibitor, alone or in combination with increasing doses of radiation from 0–8 Gy. In vitro studies preformed included; cell survival assays, MTT assay, immunoblot analysis of key proteins, FACS analysis for cell cycle, apoptosis, and gH2AX staining.
Results: We found that the combination of IR and Akt inhibition by MK-2206 is synergistic. MK-2206 inhibited both endogenous and radiation-induced Akt activation and phosphorylation of its down-stream targets. Decreased clonogenic survival was seen after 2 or 24 hours pretreatment with MK-2206 as well as decreased viability by MTT assay. Cell cycle analysis demonstrates MK-2206 decreases the proportion of cells in G2/M arrest following irradiation, as well as induced a greater proportion of apoptosis. Evaluation of the DNA damage response pathway demonstrated decreased levels of total DNA-PK, as well as a delayed DNA damage response.
Conclusions: These studies demonstrate that targeted inhibition of Akt effectively radiosensitizes p53 deficient TNBC cells lines, possibly through a synthetic lethal effect on the DNA damage response.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-09.
Abstract PL-3: Breast Radiotherapy: Fractionation and Other Fashions
Authors: Yarnold J 
Published: August 2014

Abstract
Hypofractionation, defined as the use of fraction sizes &gt;2.0 Gy, requires a reduction in the total dose delivered in 1.8–2.0 Gy fractions that takes account of the greater effect per Gy of larger fractional doses. Generations of radiation oncologists have been taught that small (≤2.0 Gy) daily fractions are always gentler on the dose-limiting healthy tissues than on the cancer, thereby optimising clinical benefit. This relationship applies at many tumour sites, but breast cancer is different. Well-designed randomised trials involving &gt;7000 women confirm that there are no advantages to using ≤2.0 Gy fractions, which spare breast cancer as much as the normal tissues. The limits of hypofractionation for whole breast/chest wall radiotherapy are under evaluation in the UK FAST Forward trial, testing 2 dose levels of a 5-fraction regimen given in 1 week against the 3-week UK standard. Hypofractionation can also be employed to match dose intensity more effectively to the spatial pattern of tumour relapse by modulating fraction size across the breast in preference to fraction number, an approach under test in the UK IMPORT HIGH trial. In marked contrast to conservative attitudes towards whole breast hypofractionation, there has been a dash to accelerated hypofractionation schedules among practitioners of partial breast radiotherapy.
The mean fractionation sensitivity of breast cancer, expressed as an α/β value, is approximately 3 Gy. The distribution around this point estimate could be wide or narrow; we don't know. The fractionation sensitivities of early responding normal tissues and cancers are postulated to reflect the responses of a limited number of target stem cell populations. Late-responding normal tissues are more complex in that multiple parenchymal and stromal cell lineages and interactions need to be considered. Despite potential complexity, a strong association between the proliferative indices of normal tissue parenchymal cells and fractionation sensitivity support the notion that the latter has a cellular basis, justifying a focus on classical cellular recovery and DNA double strand break (DSB) repair. Differences between healthy and malignant tissues in how they handle DSB are but one of several potential modulators of fractionation sensitivity. The processes are likely to be strongly affected by mutational and epigenetic alternations in tumours, but they foretell a future when predictive biomarkers replace historical dogma in determining fractionation regimens for cancer patients.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PL-3.
Abstract S3-8: Identification of Novel Synthetic-Lethal Targets for MYC-Driven Triple-Negative Breast Cancer
Authors: Goga A , Samson S , Horiuchi D 
Published: August 2014

Abstract
Currently, the greatest clinical challenge in treating breast cancer occurs in those patients whose tumors lack expression of the estrogen and progesterone receptors and the HER2 oncoprotein. No targeted agents currently exist against this aggressive type of receptor ‘triple negative’ breast cancer that disproportionately affects young African American women and also a substantial number of white American women. We have discovered that triple-negative tumors frequently express high levels of the MYC proto-oncogene. We sought to identify new “synthetic-lethal” strategies to selectively kill triple-negative breast tumors with MYC overexpression. Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes has little effect. Using this strategy, we can take advantage of the elevated MYC signaling in triple-negative tumors to selectively kill them, while sparing normal tissues in which MYC is expressed at much lower levels.
RESULTS: We performed a shRNA synthetic-lethal screen to identify new molecules, such as cell cycle kinases, which when inhibited can preferentially kill triple-negative breast tumor cells. The unbiased shRNA-based screening approach was performed in human mammary epithelial cells (HMECs) that have inducible MYC over-expression. A high-throughput screen of ∼2000 shRNAs, that target the human kinome (∼ 600 kinases) was performed, and identified 13 kinases whose inhibition by &gt;1 shRNAs gave rise to &gt;50% inhibition of cell growth. Two of the kinases identified in our screen, ARK5 and GSK3A, were also recently identified by other studies and shown to have a synthetic-lethal interaction with MYC. These results validated our ability to identify synthetic-lethal targets. We are currently characterizing and validating the 11 novel targets identified in this screen, using human cancer cell lines as well as mouse cancer models to determine the impact of inhibiting these targets on triple-negative breast cancer development and proliferation. Additional synthetic-lethal interactions with MYC over-expression in triple-negative breast cancers will be presented.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-8.
Abstract ES06-2: The impact of biological age
Authors: Ring A 
Published: August 2014

Abstract
The prognosis of a woman with early breast cancer is dependent on both tumor and patient characteristics. Tumor-related prognostic factors, such as stage, grade, and biomarker expression are well-described in the breast cancer literature and remain the focus of considerable ongoing research efforts. However patient-related factors which may influence risks of death from competing causes of mortality or tolerance of adjuvant therapies receive less attention. Risks of death from other causes and likely tolerance of treatment are particularly important considerations in the management of the increasing number of older women who are now presenting with early breast cancer. Chronological age itself may be a useful predictor of these outcomes. However older patients represent a heterogeneous population in terms of co-morbidities, fitness, life expectancy, social situation, cognitive function as well as desire for treatment. Therefore an objective definition of “biological age” might be a more accurate predictor. Those involved in the care of older patients have therefore developed “Comprehensive Geriatric Assessments” (CGAs) which are based on questionnaires or simple physical measurements which may describe “biological age”. Furthermore blood-based biomarkers of biological age have also been developed. Co-morbidity is one component of a holistic patient assessment which has been shown to be a useful predictor of risk of death before recurrence in women with breast cancer (1). In addition questionnaires derived from CGAs may be good predictors of treatment tolerance in patients receiving chemotherapy (2). Ongoing studies are evaluating whether more extensive assessments, incorporating more domains of a CGA, such as functional status, cognitive function and nutrition add to the predictive model. Any incorporation of such measures into routine clinical practice will require further validation and confirmation of clinical utility. Nonetheless such tools assessing biological age do offer the promise to improve further on the advances made in personalising adjuvant therapies that pathological and molecular tumor characterisation have already achieved. As such it seems likely that assessment of these factors in order to more objectively take into account the risks of death from competing causes of mortality and likely tolerance of treatment will become core components to informed adjuvant treatment decisions in the future.
1. Ring A et al. J Clin Onc 2011; 29:4266-4272
2. Hurria A et al. J Clin Onc 2011;29:3457-3465.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES06-2.
Abstract MS01-1: Using T cell receptor engineered T cells for the treatment of cancer
Authors: Morgan RA 
Published: August 2014

Abstract
Adoptive cellular immunotherapy involves the administration of autologous or allogenic tumor reactive T cells into patients to achieve tumor regression and has been successful in transplant-related malignancies, leukemia, and melanoma. The molecule responsible for the recognition of tumor antigens is the T cell receptor (TCR). Best studied in melanoma, this process involves the identification of lymphocytes with high affinity for tumor antigens that can be selected in vitro and expanded and administered to patients. The administration of naturally occurring T cells has been shown to have an objective response rate ranging from 50-70% in metastatic melanoma patients; including bulky invasive tumors at multiple sites including liver, lung, soft tissue and brain. A major limitation to the widespread application of adoptive cell therapy is the difficulty in generating human T cells with anti-tumor reactivity. To overcome this limitation, we can now insert highly active TCR genes into T cells that can recognize tumor antigens. Genetic engineering of TCR genes into normal T cells is a powerful new strategy to generate large numbers of defined antigen-specific cells for therapeutic application. This approach has evolved beyond experimental stage into a clinical reality. The feasibility of TCR engineered T cells has been shown to be an effective clinical strategy resulting in the regression of established tumors in recent clinical trials. Ultimately it may be possible to establish a collection of defined TCR genes that could be used to treat a diverse set of cancers tailored to each patient depending on the expression pattern of their tumor antigens.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr MS01-1.
Abstract MS02-1: HER2+ breast cancer: Unresolved challenges
Authors: Winer EP 
Published: August 2014

Abstract
Dramatic advances have been made in the treatment of HER2+ breast cancer over the past 15 years. As a result of HER2-directed therapy, survival in the both the early stage and metastatic settings has improved substantially. This improvement in survival has been accompanied by decreases in treatment-associated toxicity and improvements in quality of life. In spite of these advances, numerous challenges remain. Metastatic HER2+ disease remains incurable, and the vast majority of women with HER2+ metastatic disease ultimately succumb to their illness. In the setting of early stage disease, there is a need to identify which patients require more treatment than the present standard, which would do equally well with less, and which patients need an entirely different treatment program. Clinical data strongly suggest that HER2+ breast cancer is not a monolithic force. A better understanding of the underlying heterogeneity of HER2+ breast cancer is needed, and this understanding will assist in answering many of the unresolved questions. The most critical clinical challenges include: 1) What approaches can be used to delay and ultimately avoid drug resistance? 2) How can we treat and/or prevent brain metastases? 3) Which patients can be treated with adjuvant regimens that minimize or entirely avoid chemotherapy? 4) What is the optimal treatment for patients with small tumors and negative lymph nodes? 5) What trial designs are needed the vast majority of patients are doing well and recurrence rates are very low, but there is still some room for improvement. If we are going to eliminate mortality from HER2+ breast cancer, creative, collaborative, and multidisciplinary, approaches will be needed.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr MS02-1.
Abstract OT2-6-14: Phase 2, single arm study of a steroid-based mouthwash to prevent stomatitis in women with hormone receptor–positive advanced breast cancer treated with everolimus plus exemestane
Authors: Rugo HS , Chambers MS , Litton J , Mayer I , Rogerio J , Demars L , Geronimo J , Warsi G , Meiller TF 
Published: August 2014

Abstract
BACKGROUND: Stomatitis, the inflammation of mucous membranes lining the mouth and throat, is a frequent adverse event that is associated with the oral mTOR inhibitor everolimus and can significantly impact treatment adherence. Specific strategies to prevent and/or lessen the severity of everolimus-associated stomatitis are not well documented. Steroid mouthwashes and steroid gels or pastes used to treat recurrent aphthous stomatitis may be effective for stomatitis associated with everolimus. This phase 2, single-arm study will evaluate a steroid-based therapeutic intervention to prevent stomatitis (Grade ≥2) in breast cancer patients taking everolimus + exemestane.
METHODS: Eligible participants will be patients with HR-positive, HER2-negative advanced breast cancer with no evidence of oral stomatitis or other oral pathology who have been prescribed everolimus + exemestane but have not yet started treatment. A baseline oral assessment will be conducted, and patients will be provided instructions on how to self-monitor for stomatitis, along with instructions to contact the study site at the first sign of oral pain or changes to the oral mucosa. All patients will be instructed to perform routine good oral care. Eligible patients will receive a steroid-based mouthwash (alcohol-free 0.5mg/5ml dexamethasone solution) prophylactically. Patients will be instructed to perform the mouthwash regimen four times per day and swish the mouthwash in mouth for a minimum of 120 seconds before spitting it out. Patients will be instructed to abstain from eating or drinking for at least an hour after taking the mouthwash. Mouthwash regimen will begin on the first day of everolimus after administration of the dose and patients will continue the regimen for the first 4 months of everolimus therapy.
Primary endpoint is the incidence of stomatitis (Grade ≥2) at 2 months defined as meeting at least one of the following criteria: ≤50 on Normalcy of Diet Scale to assess oral intake and a rating of 7 on two consecutive days or a rating of 8, 9 or 10 on any one day using Visual Analog Scale to assess oral pain. Evidence of stomatitis must be confirmed by investigator on physical exam and/or phone call assessment. Secondary endpoints include average number of times per day the mouthwash regimen was performed and time to resolution of stomatitis (Grade ≥2) that occurs during the trial. Assuming a 13% absolute reduction in the rate of grade ≥ stomatitis from the historical control rate of 33% and one sided Type 1 error = 0.05 and power = 80%,73 evaluable patients will be needed. To account for 25% of the total patient population being non-evaluable, 97 patients will be enrolled for this study.
Supported by funding from Novartis Pharmaceuticals Corporation.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-14.