Priscilla McAuliffe - Profile on Academia.edu (original) (raw)

Papers by Priscilla McAuliffe

Molecular Cancer Therapeutics, Oct 1, 2010

mTOR (mammalian target of rapamycin) signaling is a central regulator of protein translation, cel... more mTOR (mammalian target of rapamycin) signaling is a central regulator of protein translation, cell growth and metabolism. Alterations of the mTOR signaling pathway are common in cancer, making mTOR a promising therapeutic target. In clinical trials, rapamycin analogs have shown modest response rates for most cancer types, including breast cancer. Therefore, there is an urgent need to better understand rapamycin's mechanism of action, in order to improve patient selection and to monitor pathway inhibition. To identify novel pharmacodynamic markers of rapamycin activity, we performed transcriptional profiling of total and polysome-associated RNA in three breast cancer cell lines representing different subtypes. In all three cell lines, we found that rapamycin significantly decreased polysome-associated mRNA for stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis. Activators of mTOR increased SCD1 protein expression, while rapamycin, LY294002 and BEZ235 decreased SCD1 protein expression. Rapamycin decreased total SCD1 RNA expression without inducing a significant decline in its relative polysomal recruitment (polysome/total ratio). Rapamycin did not alter SCD1 mRNA stability. Instead, rapamycin inhibited SCD1 promoter activity and decreased expression of mature transcription factor sterol regulatory element binding protein 1 (SREBP1). Eukaryotic initiation factor 4E (eIF4E) siRNA decreased both SCD1 and SREBP1 expression, suggesting SCD1 may be Requests for reprints: Funda Meric-Bernstam, M.D.,

Annals of Surgical Oncology, Oct 29, 2021

Our retrospective study () postulated that breast cancer molecular phenotype and stage were relat... more Our retrospective study () postulated that breast cancer molecular phenotype and stage were related to axillary pathologic complete response. Low clinical T stage and hormone-receptor negativity were associated with pathologically negative axilla, indicating that de-escalation of axillary staging may be safe for some. Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

JAMA network open, Apr 15, 2021

Overtreatment of early-stage breast cancer with favorable tumor biology in older patients may be ... more Overtreatment of early-stage breast cancer with favorable tumor biology in older patients may be harmful without affecting recurrence and survival. Guidelines that recommend deimplementation of sentinel lymph node biopsy (SLNB) (Choosing Wisely) and radiotherapy (RT) (National Comprehensive Cancer Network) have been published. OBJECTIVE To describe the use rates and association with disease recurrence of SLNB and RT in older women with breast cancer. DESIGN, SETTING, AND PARTICIPANTS This cohort study obtained patient and clinical data from an integrated cancer registry and electronic health record of a single health care system in Pennsylvania. The cohort was composed of consecutive female patients 70 years or older who were diagnosed with early-stage, estrogen receptor-positive, ERBB2 (formerly HER2)-negative, clinically node-negative breast cancer from January 1, 2010, to December 31, 2018, who were treated at 15 community and academic hospitals within the health system. EXPOSURES Sentinel lymph node biopsy and adjuvant RT. MAIN OUTCOMES AND MEASURES Primary outcomes were 5-year locoregional recurrence-free survival (LRFS) rate and disease-free survival (DFS) rate after SLNB and after RT. Secondary outcomes included recurrence rate, subgroups that may benefit from SLNB or RT, and use rate of SLNB and RT over time. Propensity scores were used to create 2 cohorts to separately evaluate the association of SLNB and RT with recurrence outcomes. Cox proportional hazards regression model was used to estimate hazard ratios (HRs). RESULTS From 2010 to 2018, a total of 3361 women 70 years or older (median [interquartile range {IQR}] age, 77.0 [73.0-82.0] years) with estrogen receptor-positive, ERBB2-negative, clinically nodenegative breast cancer were included in the study. Of these women, 2195 (65.3%) received SLNB and 1828 (54.4%) received adjuvant RT. Rates of SLNB steadily increased (1.0% per year), a trend that persisted after the 2016 adoption of the Choosing Wisely guideline. Rates of RT decreased slightly (3.4% per year). To examine patient outcomes and maximize follow-up time, the analysis was limited to cases from 2010 to 2014, identifying 2109 patients with a median (IQR) follow-up time of 4.1 (2.5-5.7) years. In the propensity score-matched cohorts, no association was found between

PurposeThe purpose of this study was to examine factors associated with sleep disturbance in wome... more PurposeThe purpose of this study was to examine factors associated with sleep disturbance in women receiving adjuvant therapy for breast cancer. MethodsThis study employed a cross-sectional design using data collected at 3-months post-surgery from an ongoing longitudinal parent study. Adjuvant treatment groups included chemotherapy, radiation, aromatase inhibitor, and no adjuvant treatment. Symptoms were measured using the patient self-report measures. ResultsThe sample included 156 women diagnosed with early-stage breast cancer. There were significant differences in levels of reported sleep disturbance between treatment groups (p=0.049), with significantly higher levels of sleep disturbances in those receiving radiation compared to those receiving no adjuvant treatment (p=0.038) and in those receiving chemotherapy and those receiving no adjuvant treatment (p=0.027). Increased sleep disturbance was found to be a significant predictor for increased pain severity, nausea severity, anx...

No Special Type breast cancer (NST; commonly known as Invasive Ductal Carcinoma (IDC)) and Invasi... more No Special Type breast cancer (NST; commonly known as Invasive Ductal Carcinoma (IDC)) and Invasive Lobular Carcinoma (ILC) are the two major histological subtypes of breast cancer with significant differences in clinicopathological and molecular characteristics. The defining pathognomonic feature of ILC is loss of cellular adhesion protein, E-cadherin (CDH1). We have previously shown that E-cadherin functions as a negative regulator of the Insulin-like Growth Factor 1 Receptor (IGF1R) and propose that E-cadherin loss in ILC sensitizes cells to growth factor signaling which thus alters their sensitivity to growth factor signaling inhibitors and their downstream activators. To investigate this potential therapeutic vulnerability, we generated CRISPR-mediated CDH1 knockout (CDH1 KO) IDC cell lines (MCF7, T47D, ZR75.1) to uncover the mechanism by which loss of E-cadherin results in IGF pathway activation. CDH1 KO cells demonstrated enhanced invasion and migration that was further eleva...

SUMMARYDuctal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IB... more SUMMARYDuctal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes by analyzing 677 DCIS samples from 481 patients with 7.1 years median follow-up from the Translational Breast Cancer Research Consortium (TBCRC) 038 study and the Resource of Archival Breast Tissue (RAHBT) cohorts. We identified 812 genes associated with ipsilateral recurrence within 5 years from treatment and developed a classifier that was predictive of DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions were identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with con...

JAMA Network Open, 2021

PURPOSE: Genetic testing (GT) can identify individuals with pathogenic variants (PV) in breast ca... more PURPOSE: Genetic testing (GT) can identify individuals with pathogenic variants (PV) in breast cancer (BC) predisposition genes, who may consider contralateral risk-reducing mastectomy (CRRM). We report on CRRM rates in young women newly diagnosed with BC who received GT through a multidisciplinary clinic. METHODS: Clinical data was reviewed for patients seen between November 2014 and June 2019. Patients with non-metastatic, unilateral BC diagnosed at age ≤45 and completed GT prior to surgery were included. Associations between surgical intervention and age, BC stage, family history, and GT results were evaluated. RESULTS: Of the 194 patients, 30 (15.5%) had a PV in a BC predisposition gene (ATM , BRCA1, BRCA2, CHEK2, NBN, NF1), with 66.7% in BRCA1 or BRCA2. Of 164 (84.5%) uninformative results, 132 (68%) were negative and 32 (16.5%) were variants of uncertain significance (VUS). Overall, 67 (34.5%) had CRRM, including 25/30 (83.3%) PV carriers and 42/164 (25.6%) non-carriers. Only ...

Annals of Surgical Oncology, 2021

Endocrinology, 2020

Invasive lobular breast carcinoma (ILC) accounts for 10% to 15% of breast cancers diagnosed annua... more Invasive lobular breast carcinoma (ILC) accounts for 10% to 15% of breast cancers diagnosed annually. Evidence suggests that some aspects of endocrine treatment response might differ between invasive ductal carcinoma (IDC) and ILC, and that patients with ILC have worse long-term survival. We analyzed The Cancer Genome Atlas dataset and observed lower levels of ESR1 mRNA (P = 0.002) and ERα protein (P = 0.038) in ER+ ILC (n = 137) compared to IDC (n = 554), and further confirmed the mRNA difference in a local UPMC cohort (ILC, n = 143; IDC, n = 877; P < 0.005). In both datasets, the correlation between ESR1 mRNA and ERα protein was weaker in ILC, suggesting differential post-transcriptional regulation of ERα. In vitro, 17β-estradiol (E2) decreased the rate of degradation and increased the half-life of ERα in ILC cell lines, whereas the opposite was observed in IDC cell lines. Further, E2 failed to induce robust ubiquitination of ERα in ILC cells. To determine the potential clinica...

Oncology Nursing Forum, 2018

OBJECTIVES-This study identified women with unique trajectories of executive function, concentrat... more OBJECTIVES-This study identified women with unique trajectories of executive function, concentration, and visual working memory before and during adjuvant therapy for breast cancer, and examined phenotypic and genotypic predictors associated with subgroups. SAMPLE & SETTING-399 postmenopausal women, of whom 288 were women with earlystage breast cancer and 111 were women without breast cancer, matched on age and years of education to the women with breast cancer, and all at an urban cancer center. METHODS & VARIABLES-A repeated-measures design was used; assessments occurred before adjuvant therapy and every six months post-therapy initiation. Group-based trajectory modeling determined subgroups. Multinomial logistic regression identified phenotypic and genotypic characteristics. RESULTS-Three executive function and concentration trajectory subgroups were identified: low, moderate, and high; two visual working memory subgroups were identified: low and high. IMPLICATIONS FOR NURSING-Advancing age, greater pretherapy fatigue, and poorer pretherapy cognitive function are associated with the low subgroups. DNA repair and oxidative stress mechanisms may be involved in the cognitive changes that women experience.

American journal of clinical pathology, Jan 7, 2018

We hypothesized that prognostic accuracy of the residual disease in breast and lymph nodes (RDBN)... more We hypothesized that prognostic accuracy of the residual disease in breast and lymph nodes (RDBN) method, which is calculated using residual tumor size, nodal involvement, and tumor grade, may be improved by incorporating residual tumor cellularity. Cases included 614 patients who underwent neoadjuvant therapy for breast cancer. Tumor size was adjusted for residual cellularity of invasive carcinoma and used to calculate modified RDBN (mRDBN) and compared with unmodified gross tumor size (gRDBN). RDBN could be calculated in 428 cases. Relative risks of recurrence and death were significantly higher for RDBN-3 and RDBN-4 compared with RDBN-1. Kaplan-Meier analysis showed significant differences in disease-free survival and overall survival for estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative and ER-positive/HER2-negative subgroups (P < .0001). Both mRDBN and gRDBN provide prognostic information, particularly in HER2-negative carcinoma; howeve...

American journal of clinical pathology, Jan 31, 2018

Pathologic complete response (pCR) rate after neoadjuvant chemotherapy was compared between 141 e... more Pathologic complete response (pCR) rate after neoadjuvant chemotherapy was compared between 141 estrogen receptor (ER)-negative (43%), 41 low ER+ (13%), 47 moderate ER+ (14%), and 98 high ER+ (30%) tumors. Human epidermal growth factor receptor 2-positive cases, cases without semiquantitative ER score, and patients treated with neoadjuvant endocrine therapy alone were excluded. The pCR rate of low ER+ tumors was similar to the pCR rate of ER- tumors (37% and 26% for low ER and ER- respectively, P = .1722) but significantly different from the pCR rate of moderately ER+ (11%, P = .0049) and high ER+ tumors (4%, P < .0001). Patients with pCR had an excellent prognosis regardless of the ER status. In patients with residual disease (no pCR), the recurrence and death rate were higher in ER- and low ER+ cases compared with moderate and high ER+ cases. Low ER+ breast cancers are biologically similar to ER- tumors. Semiquantitative ER H-score is an important determinant of response to neo...

Cancer Research, 2017

Background Invasive Lobular Carcinoma (ILC) is an understudied subtype of breast cancer. Distinct... more Background Invasive Lobular Carcinoma (ILC) is an understudied subtype of breast cancer. Distinctive properties of ILC include growth patterns, metastatic behavior, receptor status (almost universally estrogen receptor (ER) positive), and survival outcomes (Long-term survival is lower in patients with ER+ ILC compared to the other main histological subtype, invasive ductal carcinoma). Our lab recently generated six long-term estrogen deprivation (LTED) models of ILC cells. We performed RNA-Sequencing on these six LTED cell lines and identified differentially expressed genes compared to their parental cells cultured with estrogen. We overlapped these results with a previously published analysis of a tamoxifen-resistant ILC cell line and found that FGFR4 is the most consistently overexpressed gene in the setting of acquired resistance to endocrine therapy in ILC cells. Hypothesis FGFR4 is an important mediator of resistance to endocrine therapy in ILC. Methods To study the role of FGF...

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Jan 26, 2017

Magee Equations were derived as an inexpensive, rapid alternative to Oncotype DX. The Magee Equat... more Magee Equations were derived as an inexpensive, rapid alternative to Oncotype DX. The Magee Equation 3 utilizes immunohistochemical and FISH data for estrogen receptor (ER), progesterone receptor (PR), HER2 and Ki-67 for its calculation (24.30812+ERIHC × (-0.02177)+PRIHC × (-0.02884)+(0 for HER2 negative, 1.46495 for equivocal, 12.75525 for HER2 positive)+Ki-67 × 0.18649). We hypothesize that Magee Equation 3 scores from pre-therapy core biopsy can predict response to neoadjuvant systemic chemotherapy. A prospectively-maintained database of patients who received neoadjuvant systemic therapy from 2010 to 2014 at a single institution was retrospectively reviewed. Pathologic complete response was defined as absence of invasive tumor in the breast and regional lymph nodes. Of the 614 cases, tumors with missing immunohistochemical results and those that were ER negative or HER2 positive were excluded. This resulted in 237 ER positive, HER2 negative/equivocal tumors that formed the basis ...

Breast cancer (Dove Medical Press), 2017

Inspired by the hypothesis that heterogeneity in the biology of breast cancers at the cellular le... more Inspired by the hypothesis that heterogeneity in the biology of breast cancers at the cellular level may account for cognitive dysfunction symptom variability in survivors, the current study explored relationships between host single-nucleotide polymorphisms (SNPs) in 25 breast cancer-related candidate genes (AURKA, BAG1, BCL2, BIRC5, CCNB1, CD68, CENPA, CMC2, CTSL2, DIAPH3, ERBB2, ESR1, GRB7, GSTM1, MELK, MKI67, MMP11, MYBL2, NDC80, ORC6, PGR, RACGAP1, RFC4, RRM2, and SCUBE2), identified from clinically relevant prognostic multigene-expression profiles for breast cancer, and pretreatment cognitive performance. The sample (n=220) was comprised of 138 postmenopausal women newly diagnosed with early stage breast cancer and 82 postmenopausal age- and education-matched healthy controls without breast cancer. Cognitive performance was assessed after primary surgery but prior to initiation of adjuvant chemotherapy and/or hormonal therapy using a comprehensive battery of neuropsychological...

Cancer medicine, Feb 1, 2017

Intertumor heterogeneity has been proposed as a potential mechanism to account for variability in... more Intertumor heterogeneity has been proposed as a potential mechanism to account for variability in cognitive performance in women diagnosed with breast cancer. The purpose of this study was to explore associations between variation in pathologic tumor features (PTFs) and variability in preadjuvant therapy cognitive performance in postmenopausal women newly diagnosed with early-stage breast cancer. Participants (N = 329) completed a comprehensive battery of neuropsychological tests to evaluate cognitive performance after primary surgery but prior to initiation of adjuvant anastrozole±chemotherapy. PTF data were abstracted from medical records. Robust multiple linear regression models were fit to estimate associations between individual PTFs and the cognitive function composite domain scores. All models controlled for age, estimated intelligence, and levels of depressive symptoms, anxiety, fatigue, and pain. Diagnosis of a HER2-positive tumor contributed to poorer verbal (b = -0.287, P...

Breast Disease, 2016

BACKGROUND: Oncotype DX R test is beneficial in predicting recurrence free survival in estrogen r... more BACKGROUND: Oncotype DX R test is beneficial in predicting recurrence free survival in estrogen receptor positive (ER+) breast cancer. Ability of the assay to predict response to neoadjuvant chemotherapy (NCT) is less well-studied. OBJECTIVE: We hypothesize a positive association between the Oncotype DX R recurrence score (RS) and the percentage tumor response (%TR) after NCT. METHODS: Pre-therapy RS was measured on core biopsies from 60 patients with ER+, HER2-invasive breast cancer (IBC) who then received NCT. Pre-therapy tumor size was measured using imaging. %TR, partial response (PR; >50%), pathologic complete response (pCR) and breast conserving surgery (BCS) rates were measured. RESULTS: Median RS was 20 (2-69). Median %TR was 42 (0-97)%. PR was observed in 43% of patients. There was no association between %TR and pre-NCT tumor size, age, Nottingham score or nodal status (p > 0.05). No statistically significant association with %TR was seen with RS as a categorical or continuous variable (p = 0.21 and 0.7, respectively). Response to NCT improved as ER (p = 0.02) by RT-PCR decreased. Lower ER expression by IHC correlated with response (p = 0.03). CONCLUSIONS: In patients with ER+ IBC receiving NCT, RS did not predict response to NCT using %TR. The benefit of the assay prior to NCT requires further study.

SpringerPlus, 2016

Purpose: The purpose of this exploratory candidate gene association study was to examine relation... more Purpose: The purpose of this exploratory candidate gene association study was to examine relationships between polymorphisms in oxidative stress and DNA repair genes and pre-adjuvant therapy cognitive function (CF) in postmenopausal women diagnosed with early stage-breast cancer. Methods: Using a neuropsychological test battery, CF was assessed in 138 women diagnosed with breast cancer prior to initiation of adjuvant therapy and 81 age-and education-matched controls and summarized across eight composites. Participants were genotyped for 39 functional or tagging single nucleotide polymorphisms (SNPs) of select oxidative stress (CAT, GPX1, SEPP1, SOD1, and SOD2) and DNA repair (ERCC2, ERCC3, ERCC5, and PARP1) genes. Multiple linear regression was used to determine if the presence or absence of one or more minor alleles account for variability in CF composite scores. Based on regression findings from the analysis of individual SNPs, weighted multi-gene, multi-polymorphism genetic risk scores (GRSs) were calculated to evaluate the collective effect of possession of multiple protective and/or risk alleles. Results: Each CF composite was significantly (p < 0.05) associated with one or more oxidative stress and DNA repair gene polymorphisms evaluated either by SNP main effects and/or SNP-by-prescribed breast cancer treatment group interactions. Each computed GRS was found to be significantly (p < 0.001) related to its corresponding CF composite. All associations were positive suggesting that as overall genetic protection increases, CF composite score increases (indicating better performance). Conclusions: These findings suggest that genetic variation in the oxidative stress and DNA repair pathways may play an important role in pre-adjuvant therapy CF in breast cancer survivors.

Annals of Surgical Oncology, 2016

Background. Neoadjuvant chemotherapy (NAC) downstages axillary disease in 55 % of node-positive (... more Background. Neoadjuvant chemotherapy (NAC) downstages axillary disease in 55 % of node-positive (N1) breast cancer. The feasibility and accuracy of sentinel lymph node biopsy (SLNB) after NAC for percutaneous biopsy-proven N1 patients who are clinically node negative (cN0) by physical examination after NAC is under investigation. ACOSOG Z1071 reported a false-negative rate of\10 % if C3 nodes are removed with dual tracer, including excision of the biopsy-proven positive lymph node (BxLN). We report our experience using radioactive seed localization (RSL) to retrieve the BxLN with SLNB (RSL/SLNB) for cN0 patients after NAC. Methods. We performed a retrospective review of a single-institution, prospectively maintained registry for the years 2013 to 2014. Patients with BxLN who received NAC and had RSL/SLNB were identified. All BxLNs were marked with a radiopaque clip before NAC to facilitate RSL. Results. Thirty patients with BxLN before NAC were cN0 after NAC and underwent RSL/SLNB. Median age was 55 years. Disease stage was IIA-IIIB. Twenty-nine of 30 had ductal cancer (12 triple negative and 16 HER-2 positive). One to 11 nodes were retrieved. Twenty-nine of 30 BxLN were successfully localized with RSL. Note was made of the BxLN-containing isotope and/or dye in 22 of