A prospective study of HER3 expression pre and post neoadjuvant therapy of different breast cancer subtypes: implications for HER3 imaging therapy guidance.

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.

Disparities in the Use of Preoperative Breast Magnetic Resonance Imaging After Breast Cancer Diagnosis.

PURPOSE: Preoperative magnetic resonance imaging (MRI) after breast cancer diagnosis is increasingly used to improve locoregional staging, particularly among women with dense breasts, extensive ductal carcinoma in situ, and lobular histology. The goals of this study were to (1) assess whether use of preoperative MRI varies by race and insurance type; and (2) determine whether preoperative MRI is associated with downstream surgical management. MATERIALS AND METHODS: We performed a retrospective cohort study of women with stage 0-III breast cancer who were treated with surgical resection within our academic health system (2016-2019). Patients were categorized by race and insurance type. The primary outcome was receipt of preoperative MRI. Secondary outcomes included surgery extent (lumpectomy v mastectomy) and receipt of a second operation. RESULTS: A total of 1,410 women (27% Black, 73% White; 67% private insurance, 26% Medicare, 6% Medicaid) were included. Black patients were significantly less likely to undergo preoperative MRI than White patients (odds ratio [OR], 0.54 [95% CI, 0.38 to 0.76]; P < .001). There was no association between insurance type and preoperative MRI (Medicare v private: OR, 0.77 [95% CI, 0.52 to 1.15]; P = .208; Medicaid v private: OR, 0.67 [95% CI, 0.36 to 1.25]; P = .210). White patients who underwent preoperative MRI were less likely to undergo lumpectomy versus those who did not (OR, 0.53 [95% CI, 0.37 to 0.76]; P < .001). Likelihood of re-excision was lower for Black women who had undergone MRI versus those who had not (OR, 0.43 [95% CI, 0.20 to 0.93]; P = .031). CONCLUSION: Black patients were less likely than White patients to undergo preoperative MRI, yet Black women who underwent MRI were less likely to require re-excision. Standardizing preoperative MRI use may mitigate provider- and system-level biases and promote more equitable care.

Racial Disparities and Strategies for Improving Equity in Diagnostic Follow-Up for Abnormal Screening Mammograms.

PURPOSE: Black and White women undergo screening mammography at similar rates, but racial disparities in breast cancer outcomes persist. To assess potential contributors, we investigated delays in follow-up after abnormal imaging by race/ethnicity. METHODS: Women who underwent screening mammography at our urban academic center from January 2015 to February 2018 and received a Breast Imaging Reporting and Data System 0 assessment were included. Kaplan-Meier estimates described distributions of time between diagnostic events from (1) screening to diagnostic imaging and (2) diagnostic imaging to biopsy. Multivariable logistic regression models estimated the associations between race/ethnicity and receipt of follow-up within 15 and 30 days. RESULTS: Two thousand five hundred and fifty-four women were included (48.6% non-Hispanic [NH] Black, 38.2% NH White, 13.1% other/unknown). Median time between screening and diagnostic imaging varied by race/ethnicity (White: 7 days [IQR, 2-14]; Black: 12 days [IQR, 7-23]; other/unknown: 9 days [IQR, 5-21]). There were similar disparities in days between diagnostic imaging and biopsy (White: 12 [IQR, 7-24]; Black: 21 [IQR, 13-37]; other/unknown: 16 [IQR, 9-30]) and between screening and biopsy (White: 20 [IQR, 11-41]; Black: 35 [IQR, 22-63]; other/unknown: 27.5 [IQR, 17-42]). After adjustment, odds of diagnostic imaging follow-up within 15 days of screening were lower for Black versus White women (odds ratio, 0.59 [95% CI, 0.44 to 0.80]; P < .001). CONCLUSION: In this diverse cohort, disparities in timely diagnostic follow-up after abnormal breast screening were observed, with Black women waiting 1.75 times as long as White women to obtain a tissue diagnosis. National guidelines for time to diagnostic follow-up may facilitate more timely breast cancer care and potentially affect outcomes.

Abbreviated Breast MRI for Supplemental Screening in Patients With Dense Breasts: Comparison of Baseline Versus Subsequent-Round Examinations.

Background: Abbreviated breast MRI (AB-MR) achieves a higher cancer detection rate (CDR) versus digital breast tomosynthesis when applied for baseline (i.e. first-round) supplemental screening in individuals with dense breasts. Limited literature has evaluated subsequent (i.e., sequential) AB-MR screening rounds. Objectives: This study aimed to compare outcomes between baseline and subsequent rounds of screening AB-MR in individuals with dense breasts at otherwise average risk of breast cancer. Methods: This retrospective study included patients with dense breasts and at otherwise average breast-cancer risk who underwent AB-MR for supplemental screening between December 20, 2016 and May 10, 2023. Clinical interpretations and results of recommended biopsies for AB-MR examinations were extracted from the EMR. Baseline and subsequent-round AB-MR examinations were compared. Results: The final sample included 2585 AB-MR examinations (2007 baseline, 578 subsequent-round) performed for supplemental screening in 2007 women (mean age, 57.1 years) with dense breasts. Among baseline examinations, 1658 (82.6%) were assessed as BI-RADS category 1 or 2, 171 (8.5%) as category 3, and 178 (8.9%) as category 4 or 5. Among subsequent-round examinations, 533 (92.2%) were assessed as BI-RADS category 1 or 2, 20 (3.5%) as category 3, and 25 (4.3%) as category 4 or 5 (p<.001). Abnormal interpretation rate (AIR) was 17.4% (349/2007) among baseline examinations, versus 7.8% (45/578) among subsequent-round examinations (p<.001). Among baseline examinations, PPV2 was 21.3% (38/178), PPV3 was 26.6% (38/143), and CDR was 18.9 per 1000 (38/2007). Among subsequent-round examinations PPV2 was 28.0% (7/25) (p=.45), PPV3 was 29.2% (7/24) (p=.81), and CDR was 12.1 per 1000 (7/578) (p=.37). All 45 cancers diagnosed by baseline or subsequent-round AB-MR were stage 0 or 1. Seven cancers diagnosed by subsequent-round AB-MR had a mean interval since prior AB-MR of 872 days, size of 0.3-1.2 cm, and node-negative status at surgical axillary evaluation. Conclusion: Subsequent rounds of AB-MR screening in individuals with dense breasts had lower AIR compared to baseline examinations while maintaining high CDR. All cancers detected by subsequent-round examinations were early-stage node-negative cancers. Clinical Impact: The findings support sequential AB-MR for supplemental screening in individuals with dense breasts. Further investigations are warranted to optimize the screening interval.

Identifying and Addressing Barriers to Screening Mammography in a Medically Underserved Community.

RATIONALE AND OBJECTIVES: Breast cancer mortality is 40% higher for Black women compared to White women. This study seeks to assess knowledge of breast cancer screening recommendations and identify barriers to risk assessment and mammographic screening among a medically underserved, low-income, predominantly Black community in West Philadelphia. MATERIALS AND METHODS: During a free mobile mammography screening event, women were offered surveys to assess perceptions of and barriers to breast cancer risk assessment and screening. Among those who subsequently underwent mobile screening, health insurance and time to additional diagnostic imaging and biopsy, when relevant, were retrospectively collected. RESULTS: 233 women completed surveys (mean age 54 ± 13 years). Ninety-three percent of respondents identified as Black. The most frequently cited barrier to screening mammography was cost and/or lack of insurance coverage (30%). Women under 50 reported more barriers to screening compared to older women. Among those recalled from screening and recommended to undergo biopsy, there was a trend toward longer delays between screening and biopsy among those without a PCP (median 45 days, IQR 25-53) compared to those with a PCP (median 24 days, IQR 16-29) (p = 0.072). CONCLUSION: In a study of a medically underserved community of primarily Black patients, barriers to breast cancer risk assessment, screening, and diagnosis were identified by self-report and by documented care delays. While free mobile mammography initiatives that bring medical professionals into communities can help mitigate barriers to screening, strategies for navigation and coordination of follow-up are critical to promote timely diagnostic resolution for all patients.

Together We Go Farther: Improving Access to Cancer Screening Through a Multidisciplinary, One-Stop-Shop Approach.

RATIONALE AND OBJECTIVES: Despite significant scientific advances in cancer treatment in recent decades, Black Americans still face marked inequities in cancer screening, diagnosis, and treatment. Redressing these persistent inequities will require innovative strategies for community engagement. Radiologists, as experts in cancer screening and diagnosis for multiple malignancies, including breast, lung, and colon, are ideally suited to lead and implement community-based strategies to address local cancer disparities. MATERIALS AND METHODS: Through an established academic-community partnership in West Philadelphia built over the course of multiple prior community healthcare events, the authors piloted a novel radiology-led multidisciplinary approach to improve access to cancer screening for the predominantly Black, medically-underserved residents. Using a "one-stop-shop" framework to provide a comprehensive suite of screening and ancillary services in the heart of the community, the authors sought to remove as many impediments to screening as possible. RESULTS: Approximately 350 participants attended the health fair, and a total of 232 screening tests or assessments were completed. Data from this event suggest that this inclusive approach, as well as the use of a health fair "passport" to incentivize engagement, can successfully improve access to screening and follow-up in an underserved community. CONCLUSION: This "one-stop-shop" community approach can be replicated by radiology-led teams in other settings as a high-value, scalable opportunity to reduce disparities in access to cancer screening.

18F-Fluoroestradiol: Current Applications and Future Directions.

In the United States, breast cancer is the second leading cause of cancer death in all women and the leading cause of cancer death in Black women. The breast cancer receptor profile, assessed with immunohistochemical staining of tissue samples, allows prediction of outcomes and direction of patient treatment. Approximately 80% of newly diagnosed breast cancers are hormone receptor (HR) positive, which is defined as estrogen receptor (ER) and/or progesterone receptor (PR) positive. Patients with ER-positive disease can be treated with therapies targeting the ER; however, the assessment of ER expression with immunohistochemical staining of biopsy specimens has several limitations including sampling error, false-negative results, challenging or inaccessible biopsy sites, and the inability to synchronously and serially assess all metastatic sites to identify spatial and/or temporal ER heterogeneity. In May 2020, after decades of research, the U.S. Food and Drug Administration approved the PET radiotracer fluorine 18 (18F) fluoroestradiol (FES) for clinical use in patients with ER-positive recurrent or metastatic breast cancer as an adjunct to biopsy. FES binds to the ER in the nucleus of ER-expressing cells, enabling whole-body in vivo assessment of ER expression. This article is focused on the approved uses of FES in the United States, including identification of a target lesion for confirmatory biopsy, in vivo assessment of biopsy-proven ER-positive disease, and evaluation of spatial and temporal ER heterogeneity. FES is an example of precision medicine that has been leveraged to optimize the care of patients with breast cancer. © RSNA, 2023 See the invited commentary by Fowler in this issue. Quiz questions for this article are available through the Online Learning Center.

Mammographic Breast Density: Current Assessment Methods, Clinical Implications, and Future Directions.

Mammographic breast density is widely accepted as an independent risk factor for the development of breast cancer. In addition, because dense breast tissue may mask breast malignancies, breast density is inversely related to the sensitivity of screening mammography. Given the risks associated with breast density, as well as ongoing efforts to stratify individual risk and personalize breast cancer screening and prevention, numerous studies have sought to better understand the factors that impact breast density, and to develop and implement reproducible, quantitative methods to assess mammographic density. Breast density assessments have been incorporated into risk assessment models to improve risk stratification. Recently, novel techniques for analyzing mammographic parenchymal complexity, or texture, have been explored as potential means of refining mammographic tissue-based risk assessment beyond breast density.

The Landmark Series-Addressing Disparities in Breast Cancer Screening: New Recommendations for Black Women.

Randomized, clinical trials have established the efficacy of screening mammography in improving survival from breast cancer for women through detection of early, asymptomatic disease. However, disparities in survival rates between black women and women from other racial and ethnic groups following breast cancer diagnosis persist. Various professional groups have different, somewhat conflicting, guidelines with regards to recommended age for commencing screening as well as recommended frequency of screening exams, but the trials upon which these recommendations are based were not specifically designed to examine benefit among black women. Furthermore, these recommendations do not appear to incorporate the unique epidemiological circumstances of breast cancer among black women, including higher rates of diagnosis before age 40 years and greater likelihood of advanced stage at diagnosis, into their formulation. In this review, we examined the epidemiologic and socioeconomic factors that are associated with breast cancer among black women and assess the implications of these factors for screening in this population. Specifically, we recommend that by no later than age 25 years, all black women should undergo baseline assessment for future risk of breast cancer utilizing a model that incorporates race (e.g., Breast Cancer Risk Assessment Tool [BCRAT], formerly the Gail model) and that this assessment should be conducted by a breast specialist or a healthcare provider (e.g., primary care physician or gynecologist) who is trained to assess breast cancer risk and is aware of the increased risks of early (i.e., premenopausal) and biologically aggressive (e.g., late-stage, triple-negative) breast cancer among black women.

Novel applications of molecular imaging to guide breast cancer therapy.

The goals of precision oncology are to provide targeted drug therapy based on each individual's specific tumor biology, and to enable the prediction and early assessment of treatment response to allow treatment modification when necessary. Thus, precision oncology aims to maximize treatment success while minimizing the side effects of inadequate or suboptimal therapies. Molecular imaging, through noninvasive assessment of clinically relevant tumor biomarkers across the entire disease burden, has the potential to revolutionize clinical oncology, including breast oncology. In this article, we review breast cancer positron emission tomography (PET) imaging biomarkers for providing early response assessment and predicting treatment outcomes. For 2-18fluoro-2-deoxy-D-glucose (FDG), a marker of cellular glucose metabolism that is well established for staging multiple types of malignancies including breast cancer, we highlight novel applications for early response assessment. We then review current and future applications of novel PET biomarkers for imaging the steroid receptors, including the estrogen and progesterone receptors, the HER2 receptor, cellular proliferation, and amino acid metabolism.

Management Strategies for Patients Presenting With Symptomatic Lymphadenopathy and Breast Edema After Recent COVID-19 Vaccination.

Ipsilateral axillary lymphadenopathy is a well-documented finding associated with COVID-19 vaccination. Varying guidelines have been published for the management of asymptomatic patients who have a history of recent vaccination and present with incidental lymphadenopathy at screening mammography. Some experts recommend follow-up imaging, and others suggest that clinical management, rather than repeat imaging or biopsy, is appropriate. Symptomatic patients with lymphadenopathy and/or additional abnormal imaging findings should be treated differently depending on risk factors and clinical scenarios. Although ipsilateral lymphadenopathy is well documented, ipsilateral breast edema after COVID-19 vaccination has been rarely reported. The combination of ipsilateral lymphadenopathy and diffuse breast edema after COVID-19 vaccination presents a clinical management challenge because edema can obscure underlying abnormalities at imaging. For symptomatic patients with lymphadenopathy and associated breast parenchymal abnormality, prompt action is appropriate, including diagnostic evaluation and consideration of tissue sampling. This approach may prevent delays in diagnosis and treatment of patients with malignancy masked by symptoms from the vaccination.

Outcomes of COVID-19 Vaccination-Related Incidental Axillary Adenopathy in Women Undergoing Breast MRI.

OBJECTIVE: To assess the frequency, management, and early outcomes of COVID-19 vaccine-related adenopathy on breast MRI. METHODS: This IRB-exempt retrospective study reviewed patients who underwent breast MRI following COVID-19 vaccine approval in the U.S. from December 14, 2020, to April 11, 2021 (N = 1912) and compared patients who underwent breast MRI the year prior to the pandemic, March 13, 2019, to March 12, 2020 (N = 5342). Study indication, patient age, date of study, date and type of vaccination(s), time difference between study and vaccinations, lymph node-specific and overall management recommendations, and outcomes of additional examinations were recorded. Differences in the final assessment categories between the subjects scanned pre-pandemic and post-vaccine were compared using the Fisher exact test. RESULTS: Vaccine-related adenopathy was mentioned in 67 breast MRI reports; only 1 in the pre-pandemic group. There were no clinically relevant differences in patient demographics between groups. There was a statistically significant increase in BI-RADS 0 assessments between the pre-pandemic and post-vaccine approval groups-0.8% (45/5342) versus 1.8% (34/1912) (P = 0.001) and BI-RADS 3 assessments-6.5% (348/5342) versus 9.2% (176/1912) (P < 0.0001). Of the 29 patients who underwent additional imaging (range, 2-94 days following MRI) and the 2 patients who underwent biopsy, 47% (31/66), none were found to have malignant adenopathy. CONCLUSION: COVID-19 vaccination is associated with transient axillary adenopathy of variable duration. This leads to additional imaging in women undergoing breast MRI, so far with benign outcomes, and this may affect audits of outcomes of MRI.

Systematic tissue collection during clinical breast biopsy is feasible, safe and enables high-content translational analyses.

Systematic collection of fresh tissues for research at the time of diagnostic image-guided breast biopsy has the potential to fuel a wide variety of innovative studies. Here we report the initial experience, including safety, feasibility, and laboratory proof-of-principle, with the collection and analysis of research specimens obtained via breast core needle biopsy immediately following routine clinical biopsy at a single institution over a 14-month period. Patients underwent one or two additional core biopsies following collection of all necessary clinical specimens. In total, 395 patients were approached and 270 consented to the research study, yielding a 68.4% consent rate. Among consenting patients, 238 lesions were biopsied for research, resulting in 446 research specimens collected. No immediate complications were observed. Representative research core specimens showed high diagnostic concordance with clinical core biopsies. Flow cytometry demonstrated consistent recovery of hundreds to thousands of viable cells per research core. Among a group of HER2 + tumor research specimens, HER2 assessment by flow cytometry correlated highly with immunohistochemistry (IHC) staining, and in addition revealed extensive inter- and intra-tumoral variation in HER2 levels of potential clinical relevance. Suitability for single-cell transcriptomic analysis was demonstrated for a triple-negative tumor core biopsy, revealing substantial cellular diversity in the tumor immune microenvironment, including a prognostically relevant T cell subpopulation. Thus, collection of fresh tissues for research purposes at the time of diagnostic breast biopsy is safe, feasible and efficient, and may provide a high-yield mechanism to generate a rich tissue repository for a wide variety of cross-disciplinary research.

Management of Unilateral Axillary Lymphadenopathy Detected on Breast MRI in the Era of COVID-19 Vaccination.

Early clinical experience with COVID-19 vaccination suggests that approved COVID-19 vaccines cause a notably higher incidence of axillary lymphadenopathy on breast MRI compared with other vaccines. Guidelines are needed to appropriately manage unilateral axillary lymphadenopathy detected by MRI in the era of COVID-19 vaccination and to avoid biopsies of benign reactive nodes. This article examines the available data on vaccine-related lymphadenopathy and offers a basic strategy for assessing axillary lymphadenopathy on MRI and guiding management. At our institution, we are adding questions regarding the date(s) and laterality of administration of COVID-19 vaccination to the intake form given to patients before all breast imaging examinations. We consider MRI-detected isolated unilateral axillary lymphadenopathy ipsilateral to the vaccination arm to most likely be related to the COVID-19 vaccine if it develops within 4 weeks of administration of either dose. In these cases, we assess the lymphadenopathy as BI-RADS 3 and recommend that follow-up ultrasound be performed within 6-8 weeks after administration of the second dose. These guidelines may be refined as we acquire further data on the expected time course of axillary lymphadenopathy after COVID-19 vaccination. Until that time, this management pathway will help avoid unnecessary biopsies of benign vaccine-related reactive lymphadenopathy.

The adjuvant use of capecitabine for residual disease following pre-operative chemotherapy for breast cancer: Challenges applying CREATE-X to a US population.

INTRODUCTION: The CREATE-X study, conducted in Japan and South Korea, established capecitabine as an adjuvant treatment option for patients with triple negative breast cancer (TNBC) who have residual disease (RD) following neoadjuvant anthracycline or taxane-based chemotherapy. However, there are no reports on the tolerability and outcomes of adjuvant capecitabine in the US setting following publication of the CREATE-X data. METHODS: We retrospectively collected treatment and tolerability data from the medical records of the first 23 TNBC patients who received adjuvant capecitabine for RD post neoadjuvant chemotherapy at our institution. Disease-free survival was assessed using the Kaplan-Meier method. RESULTS: The median starting dosage of capecitabine was 1871 mg/m2/day, most commonly divided into two daily doses on days 1-14 of each 21 day cycle. 34.8% of patients completed the treatment as prescribed. Side effects associated with treatment were common with 69.6% of patients experiencing hand-foot syndrome, 39.1% of patients experiencing diarrhea, and 13.0% of patients requiring hospitalization for side effects. Of 23 patients treated with adjuvant capecitabine, 34.8% completed the planned dose, 30.4% completed with dose reduction, and 34.8% discontinued early. At a median follow-up time of 14 months, the median disease-free survival was 22 months, with 30.4% of patients experiencing recurrence. CONCLUSION: Tolerability was poor overall compared to the CREATE-X cohort. Administering adjuvant capecitabine for TNBC patients with residual disease in the United States is challenging given differences in tolerability. More research is needed to understand how poor tolerability will affect the efficacy of this approach in the US population.

Update on Quantitative Imaging for Predicting and Assessing Response in Oncology.

Molecular imaging has revolutionized clinical oncology by imaging-specific facets of cancer biology. Through noninvasive measurements of tumor physiology, targeted radiotracers can serve as biomarkers for disease characterization, prognosis, response assessment, and predicting long-term response/survival. In turn, these imaging biomarkers can be utilized to tailor therapeutic regimens to tumor biology. In this article, we review biomarker applications for response assessment and predicting long-term outcomes. 18F-fluorodeoxyglucose (FDG), a measure of cellular glucose metabolism, is discussed in the context of lymphoma and breast and lung cancer. FDG has gained widespread clinical acceptance and has been integrated into the routine clinical care of several malignancies, most notably lymphoma. The novel radiotracers 16α-18F-fluoro-17ß-estradiol and 18F-fluorothymidine are reviewed in application to the early prediction of response assessment of breast cancer. Through illustrative examples, we explore current and future applications of molecular imaging biomarkers in the advancement of precision medicine.