Abstract Purpose HER3, a member of the EGFR receptor family, plays a central role in driving oncogenic cell proliferation in breast cancer. Novel HER3 therapeutics are showing promising results while ...recently developed HER3 PET imaging modalities aid in predicting and assessing early treatment response. However, baseline HER3 expression, as well as changes in expression while on neoadjuvant therapy, have not been well-characterized. We conducted a prospective clinical study, pre- and post-neoadjuvant/systemic therapy, in patients with newly diagnosed breast cancer to determine HER3 expression, and to identify possible resistance mechanisms maintained through the HER3 receptor. Experimental design The study was conducted between May 25, 2018 and October 12, 2019. Thirty-four patients with newly diagnosed breast cancer of any subtype (ER ± , PR ± , HER2 ±) were enrolled in the study. Two core biopsy specimens were obtained from each patient at the time of diagnosis. Four patients underwent a second research biopsy following initiation of neoadjuvant/systemic therapy or systemic therapy which we define as neoadjuvant therapy. Molecular characterization of HER3 and downstream signaling nodes of the PI3K/AKT and MAPK pathways pre- and post-initiation of therapy was performed. Transcriptional validation of finings was performed in an external dataset (GSE122630). Results Variable baseline HER3 expression was found in newly diagnosed breast cancer and correlated positively with pAKT across subtypes (r = 0.45). In patients receiving neoadjuvant/systemic therapy, changes in HER3 expression were variable. In a hormone receptor-positive (ER +/PR +/HER2-) patient, there was a statistically significant increase in HER3 expression post neoadjuvant therapy, while there was no significant change in HER3 expression in a ER +/PR +/HER2+ patient. However, both of these patients showed increased downstream signaling in the PI3K/AKT pathway. One subject with ER +/PR −/HER2− breast cancer and another subject with ER +/PR +/HER2 + breast cancer showed decreased HER3 expression. Transcriptomic findings, revealed an immune suppressive environment in patients with decreased HER3 expression post therapy. Conclusion This study demonstrates variable HER3 expression across breast cancer subtypes. HER3 expression can be assessed early, post-neoadjuvant therapy, providing valuable insight into cancer biology and potentially serving as a prognostic biomarker. Clinical translation of neoadjuvant therapy assessment can be achieved using HER3 PET imaging, offering real-time information on tumor biology and guiding personalized treatment for breast cancer patients.
To prospectively determine cancer yield, callback and biopsy rates, and positive predictive value (PPV) of mammography, magnetic resonance (MR) imaging, and ultrasonography (US) in women at high risk ...for breast cancer.
The study was approved by the institutional review board and was HIPAA compliant, and informed consent was obtained. We conducted a prospective pilot study of screening mammography, MR, and US in asymptomatic women 25 years of age or older who were genetically at high risk, defined as BRCA1/BRCA2 carriers or with at least a 20% probability of carrying a BRCA1/BRCA2 mutation. All imaging modalities were performed within 90 days of each other. Data were analyzed by using exact confidence intervals (CIs) and the McNemar test.
A total of 195 women were enrolled in this study over a 6-month period, and 171 completed all study examinations (mammography, US, and MR). Average age of the 171 participants was 46 years +/- 10.2 (standard deviation). Sixteen biopsies were performed and six cancers were detected, for an overall 3.5% cancer yield. MR enabled detection of all six cancers; mammography, two; and US, one. The diagnostic yields for each test were 3.5% for MR, 0.6% for US, and 1.2% for mammography. MR, US, and mammography findings prompted biopsy in 8.2%, 2.3%, and 2.3% of patients, respectively. None of the pairwise comparisons were statistically significant. The PPV of biopsies performed as a result of MR was 43%.
Screening MR imaging had a higher biopsy rate but helped detect more cancers than either mammography or US. US had the highest false-negative rate compared with mammography and MR, enabling detection of only one in six cancers in high-risk women.
Our aim was to determine upgrade rates of pure flat epithelial atypia (FEA) to malignancy and higher-risk lesions and to identify patients with FEA at low risk for upgrade.
Medical chart review from ...2007 to 2016 identified 208 consecutive patients with pure FEA diagnosed by image-guided core needle biopsy who underwent surgical excision (96.2% 200 of 208) or had at least 2 years of imaging follow-up (3.8% 8 of 208). Medical records were reviewed for risk factors and surgical outcomes.
Overall upgrade rate of FEA to malignancy was 2.4% (5 of 208). All 5 upgraded cases were ductal carcinoma in situ at operation. The upgrade rate to atypical ductal hyperplasia, lobular carcinoma in situ, or atypical lobular hyperplasia was 29.8% (62 of 208). The FEA lesions in patients with a genetic mutation were more likely to upgrade to malignancy than FEA lesions in patients without a genetic mutation (33.3% 1 of 3 vs 2.0% 4 of 205; p < 0.01). The FEA lesions in patients with a personal history of breast cancer were more likely to upgrade to higher-risk lesions than those without a personal history (47.8% 11 of 23 vs 27.6% 51 of 185; p = 0.046) but were not more likely to be upgraded to malignancy (0% 0 of 23 vs 2.7% 5 of 185; p = 0.42).
The overall risk of upgrade of FEA to malignancy is low at 2.4%; however, the upgrade rate to a higher-risk lesion is nearly 30%. Surveillance rather than surgical excision of FEA can be a reasonable option for patients without a genetic mutation who opt against chemoprevention.
The purpose of this study is to evaluate the feasibility and effectiveness of a nonradioactive magnetic marker wireless localization technique.
A retrospective review was performed of consecutive ...patients who underwent image-guided needle localization with nonradioactive magnetic markers and subsequent surgical excision from March to August 2017. Indications for marker placement, lesion type, imaging guidance used for marker placement, postprocedure mammographic imaging and reports, surgical reports, and surgical margin status were reviewed.
A total of 188 patients (mean age, 59 years; range, 22-89 years) underwent image-guided localization with 213 magnetic markers and subsequent surgical excision. The indications for marker placement included invasive carcinoma (96 markers 45.1%), ductal carcinoma in situ (41 markers 19.2%), and high-risk lesions (71 markers 33.3%). Localization markers were most commonly placed for masses (96 markers 45.1%) and were deployed under mammographic guidance (160 markers 75.1%) or sonographic guidance (53 markers 24.9%). Technical success, which was defined as placement of the magnetic marker within 1 cm of the target, was achieved for 206 of 213 markers (96.7%). All 213 markers were successfully retrieved at surgery. Of 137 cases of in situ or invasive carcinoma, 30 (21.9%) had tumor-positive or close surgical margins that required reexcision. No major or minor complications were observed during marker placement, intraoperatively, or postoperatively.
Image-guided needle localization with magnetic markers is a safe, feasible, and effective method for localizing breast lesions. Magnetic marker localization has the potential to replace conventional wire needle localization and radioactive seed needle localization for lesions that require surgical excision.
Objectives
To compare performance metrics between digital 2D mammography (DM) and digital breast tomosynthesis (DBT) in the diagnostic setting.
Methods
Consecutive diagnostic examinations from August ...2008 to February 2011 (DM group) and from January 2013 to July 2015 (DM/DBT group) were reviewed. Core biopsy and surgical pathology results within 365 days after the mammogram were collected. Performance metrics, including cancer detection rate (CDR), abnormal interpretation rate (AIR), positive predictive value (PPV) 2, PPV3, sensitivity, and specificity were calculated. Multivariable logistic regression models were fit to compare performance metrics in the DM and DM/DBT groups while adjusting for clinical covariates.
Results
A total of 22,883 mammograms were performed before DBT integration (DM group), and 22,824 mammograms were performed after complete DBT integration (DM/DBT group). After adjusting for multiple variables, the CDR was similar in both groups (38.2 per 1,000 examinations in the DM/DBT group versus 31.3 per 1,000 examinations in the DM group,
p
= 0.14); however, a higher proportion of cancers were invasive rather than in situ in the DM/DBT group 83.7% (731/873) versus 72.3% (518/716),
p
< 0.01. The AIR was lower in the DM/DBT group (
p
< 0.01), and PPV2, PPV3, and specificity were higher in the DM/DBT group (all
p
= 0.01 or
p
< 0.01).
Conclusions
Complete integration of DBT into the diagnostic setting is associated with improved diagnostic performance. Increased utilization of DBT may thus result in better patient outcomes and lead to a shift in the benchmarks that have been established for DM.
Key Points
• Integration of tomosynthesis into the diagnostic setting is associated with improved performance.
• A higher proportion of cancers are invasive rather than in situ with digital breast tomosynthesis.
• Increased utilization of tomosynthesis may lead to a shift in established benchmarks.
The purpose of this study was to evaluate the frequency and cancer yield of BI-RADS category 3 lesions in baseline versus nonbaseline (those with at least one prior) MRI screening examinations.
...Consecutive MRI screening examinations performed from 2011 through 2015 were reviewed. Pearson and Wilcoxon tests were used to examine differences in age, breast density, screening indication, background parenchymal enhancement, and cancer yield between baseline and nonbaseline MRI BI-RADS category 3 assessments. Multivariate logistic regression models based on generalized estimating equations were used to assess the odds of receiving a BI-RADS 3 assessment as a function of the variables.
Of 6672 MRI screening examinations of 3214 patients, 202 examinations (3%) were assessed BI-RADS category 3. Among baseline examinations, 8% (82/983) were assessed BI-RADS 3, compared with 2% (120/5689) of nonbaseline examinations (
< 0.001). Among the total BI-RADS 3 examinations, 6% (13/202) yielded malignancy of the lesion that had been assessed BI-RADS 3; 12 of 13 cancers were stage 0 or I at diagnosis. The cancer yield of BI-RADS 3 at baseline examinations was 2% (2/82), compared with 9% (11/120) for nonbaseline examinations (
= 0.056). Ten of 13 examinations were upgraded at or before 6-month follow-up MRI.
Baseline screening breast MRI examinations are associated with a significantly higher rate of BI-RADS category 3 assessments than are nonbaseline examinations. Most cancers diagnosed at follow-up of BI-RADS 3 lesions are in an early stage and are diagnosed at or before the 6-month follow-up examination. When used judiciously, short-interval follow-up MRI is an appropriate method for identifying early-stage breast cancer while avoiding unnecessary biopsies with benign findings.
Background
Identifying women at risk for advanced interval cancers would allow better targeting of mammography and supplemental screening. The authors assessed risk factors for advanced breast cancer ...within 2 years of a negative mammogram.
Methods
The authors included 293,520 negative mammograms performed from 2006 to 2015 among 74,736 women. Breast cancers were defined as advanced if they were >2 cm, were >1 cm and triple‐negative or human epidermal growth factor receptor 2–positive, had positive lymph nodes, or were metastatic. Cox proportional hazards modeling was used to evaluate associations of age, breast density, menopause, mammogram type, prior breast biopsy, body mass index (BMI), and a family history of breast cancer with a cancer diagnosis within 2 years of a negative mammogram. Models were stratified by year since a negative mammogram.
Results
Among 1345 breast cancers, 357 were advanced (26.5%), and 988 (73.5%) were at an early stage. Breast density, prior biopsy, and family history were associated with an increased risk of both advanced and early‐stage cancers. Overweight and obese women had a 40% higher risk of early‐stage cancer only in year 2 (overweight hazard ratio HR, 1.41; 95% confidence interval CI, 1.19‐1.67; P < .001; obese HR, 1.41; 95% CI, 1.17‐1.70; P < .001). Obese women had a 90% increased risk of advanced cancer in year 1 (HR, 1.90; 95% CI, 1.14‐3.18; P = .014), and both overweight and obese women had a 40% or greater increased risk in year 2 (overweight HR, 1.55; 95% CI, 1.14‐2.07; P = .005; obese HR, 1.42; 95% CI, 1.00‐2.01; P = .051).
Conclusions
A higher BMI was associated with an advanced breast cancer diagnosis within 2 years of a negative mammogram. These results have important implications for risk assessment, screening intervals, and use of supplemental screening.
Identifying women at high risk for interval breast cancers is key for targeting screening strategies. This study has found that obesity, among other factors, is associated with advanced interval breast cancers.
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