Screening MRI Does Not Increase Cancer Detection or Result in an Earlier Stage at Diagnosis for Patients with High-Risk Breast Lesions: A Propensity Score Analysis.

BACKGROUND: Guidelines recommend consideration of screening MRI for patients with high-risk breast lesions (HRLs), acknowledging limited data for this moderate-risk population. METHODS: This study identified patients with atypical ductal/lobular hyperplasia (ADH/ALH), lobular carcinoma in situ, (LCIS) or both evaluated at our high-risk clinic. Patients were categorized as having received screening mammography (MMG) alone vs. MMG and breast MRI (MMG+MRI). Inverse probability weighting based on propensity scores (PS) representing likelihood of MRI use was applied to Kaplan-Meier and Cox regression analyses to determine cancer detection and biopsy rates by screening group. RESULTS: Among 908 eligible patients, 699 (77%) patients with available follow-up data were analyzed (542 with ADH/ALH and 157 with LCIS). Of the 699 patients, 540 (77%) received MMG alone, and 159 (23%) received MMG + MRI. The median follow-up period was 25 months, during which a median of two MRIs were performed. After PS-weighting, the characteristics of each screening group were well-balanced with respect to age, race, body mass index (BMI), menopausal status, breast density, family history, HRL type, and chemoprevention use. The 4 year breast cancer detection rate was 3.6% with both MMG alone and MMG+MRI (p = 0.89). The breast biopsy rates were significantly higher with MMG+MRI (30.5% vs12.6%; hazard ratio [HR], 2.67; p < 0.001). All breast cancers were clinically node-negative and pathologic stage 0 or 1. Among five cancers in the MMG+MRI group, two were MRI-detected, two were MMG-detected, and one was detected on clinical exam. CONCLUSIONS: Screening MRI did not improve cancer detection, and cancer characteristics were favorable whether screened with MMG alone or MMG + MRI. These findings question the benefit of MRI for patients with HRL, although longer-term follow-up study is needed.

Initiation and tolerance of chemoprevention among women with high-risk breast lesions: the potential of low-dose tamoxifen.

PURPOSE: High-risk lesions (HRLs) of the breast are an indication for chemoprevention, yet uptake is low, largely due to concerns about side effects. In 2019, low-dose (5 mg) tamoxifen was demonstrated to reduce breast cancer risk with improved tolerance. We describe chemoprevention uptake in an academic clinic before and after the introduction of low-dose tamoxifen. METHODS: Females age ≥ 35 with HRLs who established care from April 2017 through January 2020 and eligible for chemoprevention were included. Rates of chemoprevention initiation before and after the introduction of low-dose tamoxifen (pre-2019 vs. post-2019) were compared with chi-squared tests. Logistic regression identified demographic and clinical factors associated with chemoprevention initiation. Kaplan-Meier methods determined the rates of discontinuation. RESULTS: Among 660 eligible females with HRLs, 22.7% initiated chemoprevention. Median time from first visit to chemoprevention initiation was 54 days (interquartile range (IQR): 0-209); 31.0% (46/150) started chemoprevention > 6 months after their initial visit. Chemoprevention uptake was not significantly different pre-2019 vs. post-2019 (21.2% vs. 26.3%, p = 0.16); however, post-2019, low-dose tamoxifen became the most popular option (41.5%, 34/82). On multivariable analyses, age and breast cancer family history were significantly associated with chemoprevention initiation. Discontinuation rates at 1 year were lowest for low-dose tamoxifen (6.7%) vs. tamoxifen 20 mg (15.0%), raloxifene (20.4%), or an aromatase inhibitor (20.0%). CONCLUSION: In this modern cohort, 22.7% of females with HRLs initiated chemoprevention with 31.0% initiating chemoprevention > 6 months after their first visit. Low-dose tamoxifen is now the most popular choice for chemoprevention, with low discontinuation rates at 1 year.

Customized breast cancer risk assessment in an ambulatory clinic: a portal for identifying women at risk.

PURPOSE: Existing high-risk clinic models focus on patients with known risk factors, potentially missing many high-risk patients. Here we describe our experience implementing universal risk assessment in an ambulatory breast center. METHODS: Since May 2017, all breast center patients completed a customized intake survey addressing known breast cancer risk factors and lifestyle choices. Patient characteristics, family history, risk scores, and lifestyle factors were examined; patients with high-risk breast lesions were excluded. Patients were considered at increased risk by model thresholds Gail 5-year risk > 1.7% (35-59 years), Gail 5-year risk > 5.5% (≥ 60 years), or Tyrer-Cuzick (T-C) v7 lifetime risk > 20% (any age). RESULTS: From May 2017-April 2018, there were 874 eligible patients-420 (48%) referred for risk assessment (RA) and 454 (52%) for non-specific breast complaints (NSBC). Overall, 389 (45%) were at increased risk of breast cancer. Gail 5-year risks were similar between RA and NSBC patients. However, RA patients more frequently met criteria by T-C score (P = 0.02). Of all patients at increased risk, 149 (39%) were overweight (BMI > 25) or obese (BMI > 30) and only 159 (41%) met recommended exercise standards. NSBC patients who met criteria were more frequently smokers (8% vs 1%, P < 0.01); all other demographic/lifestyle factors were similar among high-risk patients regardless of referral reason. CONCLUSIONS: Universal risk assessment in a comprehensive breast health center identified 45% of our population to be at increased risk of breast cancer. This clinical care model provides a unique opportunity to identify and address modifiable risk factors among women at risk.

Coordinated regulation of ß-tubulin isotypes and epithelial-to-mesenchymal transition protein ZEB1 in breast cancer cells.

The regulation of ß-tubulin isotypes, the primary targets for antimitotic chemotherapeutic drugs like taxanes, has implications for drug response and drug resistance. Over the past 15 years, micro-RNAs have been studied widely as regulators of mRNA levels. For example, the tumor suppressor miR-200c was shown in cell culture to target mesenchymal genes, including ZEB1 [ Cochrane ( 2009 ) Mol. Cancer Ther. 8 ( 5 ), 1055 - 1066 ]. In that work, exogenous miR-200c was also shown to reduce ß-tubulin class III, one of its predicted targets. Furthermore, decreased miR-200c and increased ß-tubulin class III were associated with poor outcomes for ovarian cancer patients [ Cittelly , D.M. ( 2012 ) Mol. Cancer Ther. 11 ( 12 ), 2556 - 2565 ]. Because miR-200c targets the epithelial-to-mesenchymal inducer ZEB1, we wanted to know whether changes in ZEB1 parallel ß-tubulin isotype changes, implicating ß-tubulin isotypes in ZEB1-associated cell survival pathways. We found coordinated positive feedback regulation of mRNA for ZEB1 and ß-tubulin isotype classes I, III, and IVB in MDA-MB-231 breast cancer cells, commonly used as a model for triple-negative breast cancers. Low levels of paclitaxel (40 nM) were found to significantly reduce mRNA levels for these tubulin genes along with a 2-3-fold increase in miR-200c. ZEB1 silencing also reduced ß-tubulin isotype classes I, III, and IVB mRNA, whereas upregulation of ZEB1 was associated with increases in these isotype classes. Our work indicates that paclitaxel-induced reduction of ZEB1 and ß-tubulin isotypes are, in part, due to increased activity of miR-200c. These results suggest that in aggressive breast cancers, as modeled by MDA-MB-231 cells, ß-tubulin class III is a biomarker for cell survival mediated through ZEB1-induced tumor progression pathways.

Prognostic biomarkers for HNSCC using quantitative real-time PCR and microarray analysis: ß-tubulin isotypes and the p53 interactome.

In 2014, more than 40,000 people in the United States will be diagnosed with head and neck squamous cell cancer (HNSCC) and nearly 8400 people will die of the disease (www.cancer.org/acs/groups). Little is known regarding molecular targets that might lead to better therapies and improved outcomes for these patients. The incorporation of taxanes into the standard cisplatin/5-fluouracil initial chemotherapy for HNSCC has been associated with improved response rate and survival. Taxanes target the ß-subunit of the tubulin heterodimers, the major protein in microtubules, and halt cell division at G2/M phase. Both laboratory and clinical research suggest a link between ß-tubulin expression and cancer patient survival, indicating that patterns of expression for ß-tubulin isotypes along with activity of tumor suppressors such as p53 or micro-RNAs could be useful prognostic biomarkers and could suggest therapeutic targets. © 2014 Wiley Periodicals, Inc.

Regulation of tubulin expression by micro-RNAs: implications for drug resistance.

In this chapter, we provide an overview of methods for studying micro-RNA regulation of tubulin isotypes. In clinical studies, ß-tubulin isotypes were found to be biomarkers for tumor formation. In addition, because changes in the levels of specific ß-tubulin isotypes alter the stability of microtubules in mitotic spindles in vitro, it has been hypothesized that changes in microtubule protein levels could contribute to chemotherapy resistance. Over the past 15 years, micro-RNAs have been shown to target mRNAs in signaling pathways involved in tumor suppression, as well as tumorigenesis. Investigating micro-RNA regulation of tubulin isotypes will shed light on the mechanisms underlying the processes that implicate tubulin isotypes as biomarkers for aggressive tumors or chemotherapy resistance. The methods discussed in this chapter include the use of micro-RNA superarrays, next-generation sequencing, real-time PCR experiments, upregulation of micro-RNAs, and immunoprecipitation of RNA-induced silencing complex. We will show examples of data collected using these methods and how these data contribute to understanding paclitaxel resistance.