Lobular Neoplasia Diagnosed by MRI-Guided Breast Biopsy: Identifying Upgrade Rate to Malignancy and Outcomes of Clinical and Surgical Management.

OBJECTIVE: The aim of this study was to determine surgical and clinical outcomes of lobular neoplasia (LN) diagnosed by magnetic resonance imaging (MRI) biopsy, including upgrade to malignancy, and to assess for characteristics associated with upgrade. METHOD: A single-institution retrospective study, between 2013 and 2022, of patients with histopathological findings of LN via MRI-guided biopsy was performed using an institutional database and review of the electronic medical records. Decision for excision or surveillance was made by a multidisciplinary team per institutional practice. Patient demographics and imaging characteristics were summarized using descriptive analyses. Upgrade was defined as upgrade to cancer on surgical pathology for patients treated with excision or the development of cancer at the biopsy site during surveillance. The Wilcoxon rank-sum test and Fisher's exact test were used to compare features of the upgraded cohort with the remainder of the group. RESULTS: Ninety-four MRI biopsies diagnosing LN were included. Median age was 57 years (range 37-78 years). Forty-six lesions underwent excision while 48 lesions were surveilled. The upgrade rate was 7.4% (7/94). Upgrades in the excised cohort consisted of pleomorphic lobular carcinoma in situ (LCIS; n = 1), ductal carcinoma in situ (DCIS; n = 3) and invasive lobular carcinoma (ILC; n = 2), while one interval development of DCIS was observed at the site of biopsy in the surveillance cohort. No MRI or patient variables were associated with upgrade. CONCLUSIONS: In this contemporary cohort of MRI-detected LNs, the upgrade rate was low. Omission of surgery for MRI-detected LNs in carefully selected patients may be considered in a shared decision-making capacity between the patient and the treatment team. Larger cohorts are needed to determine factors predictive of upgrade risk.

Association between patient-surgeon race and gender concordance and patient-reported outcomes following breast cancer surgery.

PURPOSE: Surgeon- and patient-related factors have been shown to influence patient experiences, quality of life (QoL), and surgical outcomes. We examined the association between patient-surgeon race and gender concordance with QoL after breast reconstruction. METHODS: We conducted a retrospective cross-sectional analysis of patients who underwent lumpectomy or mastectomy followed by breast reconstruction over a 3-year period. We created the following categories with respect to the race and gender of a patient-surgeon triad: no, intermediate, and perfect concordance. Multivariable regression was used to correlate postoperative global (SF-12) and condition-specific (BREAST-Q) QoL performance with patient-level covariates, gender and race concordance. RESULTS: We identified 375 patients with a mean (± SD) age of 57.6 ± 11.9 years, median (IQR) body mass index of 27.5 (24.0, 32.0), and median morbidity burden of 3 (2, 4). The majority of encounters were of intermediate concordance for gender (70%) and race (52%). Compared with gender-discordant triads, intermediate gender concordance was associated with higher SF-Mental scores (ß, 2.60; 95% CI, 0.21-4.99, p = 0.003). Perfect race concordance (35% of encounters) was associated with significantly higher adjusted SF-Physical scores (ß, 2.14; 95% CI, 0.50-4.22, p = 0.045) than the race-discordant group. There were no significant associations observed between race or gender concordance and BREAST-Q performance. CONCLUSION: Race-concordant relationships following breast cancer surgery were more likely to have improved global QoL. Perfect gender concordance was not associated with variation in QoL outcomes. Policy-level interventions are needed to facilitate personalized care and optimize breast cancer surgery outcomes.

Low Rates of Local-Regional Recurrence Among Inflammatory Breast Cancer Patients After Contemporary Trimodal Therapy.

BACKGROUND: Inflammatory breast cancer (IBC) represents a rare (2-3 %) but aggressive subset of breast cancer with a historically reported 5-year overall survival rate of 50 % and a 3-year local-regional recurrence (LRR) rate of 20 %. This study aimed to evaluate long-term LRR in a contemporary cohort of non-metastatic IBC patients undergoing trimodal therapy at a single institution and identify factors associated with local and distant failure. METHODS: The study identified 262 patients with non-metastatic IBC who received trimodal therapy (neoadjuvant chemotherapy, modified radical mastectomy, adjuvant radiation) from an institutional prospective database (2007-2019). Long-term outcomes of local-regional and distant metastasis were reported. Survival outcomes were analyzed using the Cox proportional hazards regression model. RESULTS: The median age at diagnosis was 52 years, and the median follow-up period was 5.1 years. In this cohort, 82 (31.3 %) patients achieved a pathologic complete response (pCR) in the breast and axilla. Local-regional recurrence was observed in 18 (6.9 %) patients (11 isolated to the chest wall, 4 isolated to regional nodes, and 3 involving chest wall and ipsilateral axillary nodes). Distant metastasis was observed in 92 (35.1 %) patients. During the follow-up period, 90 deaths occurred. In the multivariate analysis, pCR was associated with improved disease-free survival (hazard ratio [HR], 0.26; 95 % confidence interval [CI], 0.13-0.51; p = 0.001) and overall survival (HR, 0.31; 95 % CI, 0.15-0.65; p = 002). CONCLUSIONS: During a median follow-up period longer than 5 years, the local-regional relapse rate for the IBC patients treated with contemporary trimodal therapy was 6.9%, similar to that for the non-IBC patients. After chemotherapy, surgical resection with modified radical mastectomy to negative margins and postmastectomy radiation therapy resulted in excellent long-term local-regional control.

Lymphedema in Inflammatory Breast Cancer Patients Following Trimodal Treatment.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a debilitating sequela of breast cancer treatment and is becoming a greater concern in light of improved long-term survival. Inflammatory breast cancer (IBC) is a rare and aggressive malignancy for which systemic therapy, surgery, and radiotherapy remain the standard of care, thereby making IBC patients highly susceptible to developing BCRL. This study evaluated BCRL in IBC following trimodal therapy. METHODS: IBC patients treated from 2016 to 2019 were identified from an institutional database. Patients were excluded if they presented with recurrent disease, underwent bilateral axillary surgery, did not complete trimodal therapy, or were lost to follow-up. Demographic, clinicopathologic factors, oncologic outcomes, and perometer measurements were recorded. BCRL was defined by clinician diagnosis and/or objective perometer measurements when available. Time to development of BCRL and treatment received were captured. RESULTS: Eighty-three patients were included. Median follow-up was 33 months. The incidence of BCRL was 50.6% (n = 42). Mean time to BCRL from surgery was 13 (range 2-24) months. Demographic and clinicopathologic features were similar between patients with and without BCRL with exception of higher proportion receiving delayed reconstruction in the BCRL group (38.1% vs. 14.6%, p = 0.03). Forty patients (95.2%) underwent BCRL treatment, which included physical therapy (n = 39), compression (n = 38), therapeutic lymphovenous bypass (n = 13), and/or vascularized lymph node transfer (n = 12). CONCLUSIONS: IBC patients are at high-risk for BCRL after treatment, impacting 51% of patients in this cohort. Strategies to reduce or prevent BCRL and improve real-time diagnosis should be implemented to better direct early management in this patient population.

Current Surgical Management of Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is a rare and aggressive breast cancer characterized by erythema and edema of at least one-third of the breast. The diagnosis remains a clinical one. Standard of care involves trimodality therapy with anthracycline-based neoadjuvant chemotherapy and human epidermal growth factor receptor 2 (HER2)-directed therapy if HER2 positive, followed by modified radical mastectomy and post-mastectomy radiation therapy to the chest wall in addition to regional nodal basins including supraclavicular and internal mammary nodes. Current evidence does not support de-escalation of surgical therapy in the breast and axilla in IBC, and positive surgical margins have been associated with worse outcomes. Furthermore, sentinel node biopsy for axillary staging has a high false negative rate prohibiting its use in IBC. Delayed reconstruction is recommended for IBC due to a high recurrence rate and a potential for delay in adjuvant therapy. Contralateral prophylactic mastectomy may be considered at the time of delayed reconstruction. In this paper, we discuss available evidence and controversies in the current surgical management of patients with IBC.

Inflammatory Breast Cancer at the Extremes of Age.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare breast malignancy with poor outcomes compared with non-IBC. Age-related differences in tumor biology, treatment, and clinical outcomes have been described in non-IBC. This study evaluated age-related differences in IBC. METHODS: From an institutional prospective database, patients with an IBC diagnosed from 2010 to 2019 were identified. Age was categorized as 40 years or younger, 41 to 64 years, and 65 years or older. Demographics, clinicopathologic features, and treatment received were compared. Recurrence and survival outcomes were analyzed using the log-rank test and the Cox proportional hazards model. RESULTS: Of 523 IBC patients, 113 (21.6%) were age 40 years or younger, and 72 (13.8%) were age 65 years or older. The groups did not differ statistically by race/ethnicity, N stage, clinical stage, or tumor subtype. The younger patients included a higher proportion of Hispanic and Asian patients, triple-negative breast cancer (TNBC), and clinical N2/N3. Trimodality therapy was received by 92% of the stage 3 patients, with no difference in pathologic complete response (pCR) by age (23.3% vs 28.6%; p = 0.46). During a median follow-up period of 40 months, 17% of the patients experienced locoregional recurrence and 42.8% had distant metastasis. No difference in 3-year recurrence-free survival (57.9% vs 42.6% vs 54%; p = 0.42, log rank) or overall survival (OS) (75.6% vs 77.1% vs 64.4%; p = 0.31, log rank) by age was observed, and no difference in OS by age in de novo stage 4 disease was observed. In the multivariate analysis, worse OS was associated with TNBC (hazard ratio [HR], 1.99, 95% confidence interval [CI], 1.31-3.05) and no pCR (HR, 4.45; 95% CI, 2.16-9.18). CONCLUSION: No significant differences were observed in demographics, treatment patterns, or clinical outcomes for IBC patients age 40 years or younger compared with those age 65 years or older treated by a specialized multidisciplinary team. These findings do not support age-related treatment de-escalation in IBC.

Contralateral Axillary Metastasis in Patients with Inflammatory Breast Cancer.

BACKGROUND: Nearly one-third of patients with inflammatory breast cancer (IBC) present with de novo stage IV disease. There are limited data on frequency and clinical outcomes of contralateral axillary metastasis (CAM) in IBC with no consensus diagnostic and treatment guidelines. PATIENTS AND METHODS: Frequency of synchronous CAM was calculated in unilateral IBC patients at a single center (10/2004-6/2019). Clinicopathologic variables, diagnostic evaluation, treatment received, and overall survival (OS) were assessed and compared. RESULTS: Of 588 unilateral IBC patients, 49 (8.3%) had synchronous CAM. Of these, 32 (65.3%) also presented with metastatic disease at another distant site. CAM was not associated with age, tumor laterality, breast cancer subtype, grade, or cN stage (p > 0.05). The sensitivity/specificity to detect CAM was as follows: mammography (18.2%/99.2%), ultrasound (92.3%/95.5%), PET (90.1/99.1%), and MRI (76.0%/98.6%). Following systemic therapy, 22 patients had contralateral axillary surgery, and 18 received adjuvant contralateral nodal radiation. On multivariable analysis including tumor receptor subtypes, patients with stage IV-isolated CAM has statistically similar survival to stage III patients (HR 1.37, 95% CI 0.70-2.69, p = 0.36). Patients with Stage IV non-CAM (HR 2.18, 95% CI 1.66-2.85, p < 0.001) and stage IV-CAM plus other distant metastasis (HR 2.57, 95% CI 1.59-4.16, p < 0.001) had higher risk of death (reference: stage III disease). CONCLUSIONS: CAM in IBC was diagnosed in 8.3% of patients at presentation and was best identified by ultrasound and PET. We recommend routine contralateral axillary ultrasound as part of staging for all IBC patients. Diagnosis of CAM is a key first step toward much-needed prospective clinical trials evaluating management and outcomes of CAM in IBC.

Use of Breast Imaging After Treatment for Locoregional Breast Cancer (AFT-01).

BACKGROUND: Annual mammography is recommended after breast cancer treatment. However, studies suggest its under-utilization for Medicare patients. Utilization in the broader population is unknown, as is the role of breast magnetic resonance imaging (MRI). Understanding factors associated with imaging use is critical to improvement of adherence to recommendations. METHODS: A random sample of 9835 eligible patients receiving surgery for stages 2 and 3 breast cancer from 2006 to 2007 was selected from the National Cancer Database for primary data collection. Imaging and recurrence data were abstracted from patients 90 days after surgery to 5 years after diagnosis. Factors associated with lack of imaging were assessed using multivariable repeated measures logistic regression with generalized estimating equations. Patients were censored for death, bilateral mastectomy, new cancer, and recurrence. RESULTS: Of 9835 patients, 9622, 8702, 8021, and 7457 patients were eligible for imaging at surveillance years 1 through 4 respectively. Annual receipt of breast imaging declined from year 1 (69.5%) to year 4 (61.0%), and breast MRI rates decreased from 12.5 to 5.8%. Lack of imaging was associated with age 80 years or older and age younger than 50 years, black race, public or no insurance versus private insurance, greater comorbidity, larger node-positive hormone receptor-negative tumor, excision alone or mastectomy, and no chemotherapy (p < 0.005). Receipt of breast MRI was associated with age younger than 50 years, white race, higher education, private insurance, mastectomy, chemotherapy, care at a teaching/research facility, and MRI 12 months before diagnosis (p < 0.05). CONCLUSION: Under-utilization of mammography after breast cancer treatment is associated with sociodemographic and clinical factors, not institutional characteristics. Effective interventions are needed to increase surveillance mammography for at-risk populations. ClinicalTrials.gov Identifier: NCT02171078.

A National Study of the Use of Asymptomatic Systemic Imaging for Surveillance Following Breast Cancer Treatment (AFT-01).

BACKGROUND: Although not guideline recommended, studies suggest 50% of locoregional breast cancer patients undergo systemic imaging during follow-up, prompting its inclusion as a Choosing Wisely measure of potential overuse. Most studies rely on administrative data that cannot delineate scan intent (prompted by signs/symptoms vs. asymptomatic surveillance). This is a critical gap as intent is the only way to distinguish overuse from appropriate care. OBJECTIVE: Our aim was to assess surveillance systemic imaging post-breast cancer treatment in a national sample accounting for scan intent. METHODS: A stage-stratified random sample of 10 women with stage II-III breast cancer in 2006-2007 was selected from each of 1217 Commission on Cancer-accredited facilities, for a total of 10,838 patients. Registrars abstracted scan type (computed tomography [CT], non-breast magnetic resonance imaging, bone scan, positron emission tomography/CT) and intent (cancer-related vs. not, asymptomatic surveillance vs. not) from medical records for 5 years post-diagnosis. Data were merged with each patient's corresponding National Cancer Database record, containing sociodemographic and tumor/treatment information. RESULTS: Of 10,838 women, 30% had one or more, and 12% had two or more, systemic surveillance scans during a 4-year follow-up period. Patients were more likely to receive surveillance imaging in the first follow-up year (lower proportions during subsequent years) and if they had estrogen receptor/progesterone receptor-negative tumors. CONCLUSIONS: Locoregional breast cancer patients undergo asymptomatic systemic imaging during follow-up despite guidelines recommending against it, but at lower rates than previously reported. Providers appear to use factors that confer increased recurrence risk to tailor decisions about systemic surveillance imaging, perhaps reflecting limitations of data on which current guidelines are based. ClinicalTrials.gov Identifier: NCT02171078.

Current Trends in the Management of Phyllodes Tumors of the Breast.

INTRODUCTION: National Comprehensive Cancer Network (NCCN) guidelines recommend wide excision without axillary staging to treat phyllodes tumors of the breast. Without prospective trials to guide management, NCCN also recommends consideration of radiation therapy (XRT). We describe current patterns of care for the multidisciplinary management of phyllodes tumors. METHODS: Using Surveillance, Epidemiology, and End Results Program (SEER) data, we identified women diagnosed with phyllodes tumors between 2000 and 2012 who underwent surgical therapy. Trends in breast-conserving surgery (BCS), nodal sampling, and XRT were assessed using the Cochrane-Armitage test. Multivariable logistic regression was used to identify factors associated with treatment. RESULTS: Of 1238 patients, 56.9 % underwent BCS and 23.6 % underwent nodal sampling (10.5 % after BCS vs. 40.9 % after mastectomy). After surgery, 15.4 % received adjuvant XRT (BCS 12.9 %, and mastectomy 18.8 %). XRT utilization increased significantly over the study period (BCS, p = < 0.0001; mastectomy, p = 0.0003), while nodal sampling did not change significantly. Women were more likely to receive mastectomy if they were older or had larger tumors. Nodal sampling was also associated with older age, larger tumor size, and receipt of mastectomy. Receipt of XRT was associated with later year of diagnosis, larger tumors, and nodal assessment. CONCLUSION: Over time, an increasing number of women received XRT after surgical management of phyllodes tumor, and one in four women underwent nodal sampling. While some of this practice can be attributed to concern about more advanced disease in the absence of strong data, there may be an educational gap regarding current guidelines and appropriate management.

Utility of Clinical Breast Examinations in Detecting Local-Regional Breast Events After Breast-Conservation in Women with a Personal History of High-Risk Breast Cancer.

BACKGROUND: Although breast cancer follow-up guidelines emphasize the importance of clinical examinations, prior studies suggest a small fraction of local-regional events occurring after breast conservation are detected by examination alone. Our objective was to examine how local-regional events are detected in a contemporary, national cohort of high-risk breast cancer survivors. METHODS: A stage-stratified sample of stage II/III breast cancer patients diagnosed in 2006-2007 (n = 11,099) were identified from 1217 facilities within the National Cancer Data Base. Additional data on local-regional and distant breast events, method of event detection, imaging received, and mortality were collected. We further limited the cohort to patients with breast conservation (n = 4854). Summary statistics describe local-regional event rates and detection method. RESULTS: Local-regional events were detected in 5.5 % (n = 265) of patients. Eighty-three percent were ipsilateral or contralateral in-breast events, and 17 % occurred within ipsilateral lymph nodes. Forty-eight percent of local-regional events were detected on asymptomatic breast imaging, 29 % by patients, and 10 % on clinical examination. Overall, 0.5 % of the 4854 patients had a local-regional event detected on examination. Examinations detected a higher proportion of lymph node events (8/45) compared with in-breast events (18/220). No factors were associated with method of event detection. DISCUSSION: Clinical examinations, as an adjunct to screening mammography, have a modest effect on local-regional event detection. This contradicts current belief that examinations are a critical adjunct to mammographic screening. These findings can help to streamline follow-up care, potentially improving follow-up efficiency and quality.

Discordance of Histologic Grade Between Primary and Metastatic Neuroendocrine Carcinomas.

BACKGROUND: The prognosis and management of neuroendocrine carcinoma are largely driven by histologic grade as assessed by mitotic activity. The authors reviewed their institutional experience to determine whether the histologic grade of neuroendocrine carcinoma can differ between primary and metastatic tumors. METHODS: This study examined patients who underwent operative resection of both primary and metastatic foci of neuroendocrine carcinoma. Resected tumors were independently reviewed and categorized as low, intermediate, or high grade as determined by mitotic count. RESULTS: The authors identified 20 patients with metastatic neuroendocrine carcinoma treated at their institution between 1997 and 2013 for whom complete pathologic review of primary and metastatic tumors was possible. Primary lesions were found in the small intestine (n = 12), pancreas (n = 7), ampulla (n = 1), stomach (n = 1), and rectum (n = 1). The timing of hepatic metastasis was synchronous in 15 cases and metachronous in 5 cases. The histologic grade was concordant between primary and metastatic tumors in 9 cases and discordant in 11 cases. Among the discordant cases, 7 had a higher metastatic grade than primary grade, and 4 had a lower metastatic grade than primary grade. Metachronous presentation was associated with a higher likelihood of grade discordance (p = 0.03). The histologic grade of all metachronous metastases differed from that of the primary tumors. CONCLUSION: There is a high prevalence of histologic grade discordance between primary and metastatic foci of neuroendocrine carcinoma, particularly among patients with a metachronous metastatic presentation. Given the importance of histologic grade in disease prognostication and treatment planning, this finding may be informative for the management of patients with metastatic neuroendocrine carcinoma.

Exploring Novel Frontiers: Leveraging STAT3 Signaling for Advanced Cancer Therapeutics.

Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in diverse physiologic processes, including cell proliferation, differentiation, angiogenesis, and survival. STAT3 activation via phosphorylation of tyrosine and serine residues is a complex and tightly regulated process initiated by upstream signaling pathways with ligand binding to receptor and non-receptor-linked kinases. Through downstream deregulation of target genes, aberrations in STAT3 activation are implicated in tumorigenesis, metastasis, and recurrence in multiple cancers. While there have been extensive efforts to develop direct and indirect STAT3 inhibitors using novel drugs as a therapeutic strategy, direct clinical application remains in evolution. In this review, we outline the mechanisms of STAT3 activation, the resulting downstream effects in physiologic and malignant settings, and therapeutic strategies for targeting STAT3. We also summarize the pre-clinical and clinical evidence of novel drug therapies targeting STAT3 and discuss the challenges of establishing their therapeutic efficacy in the current clinical landscape.

Long-Term Outcomes and Predictors of Response in Breast Cancer Patients with Advanced Nodal Involvement.

BACKGROUND: Advanced nodal disease is associated with poor prognosis. However, modern neoadjuvant systemic therapy (NST) regimens have resulted in higher pathologic complete response (pCR) rates, which are associated with improved survival. We sought to assess contemporary outcomes in patients with advanced nodal involvement and response to NST. STUDY DESIGN: We conducted a single-institution, retrospective study of 521 patients with cN2-3 primary nonmetastatic breast cancer treated with NST followed by surgery and radiation from 2012 to 2018. Descriptive statistics, multivariate Cox regression, and Kaplan-Meier analyses were performed. RESULTS: The mean age was 50.5 years, and median follow-up was 61 (4.7 to 197) months. The majority of patients had hormone receptor-positive (HR+)/HER2-negative tumors (HER2-; n = 242, 47.8%). Most were cT2 (n = 243; 46.6%) or cT3 (n = 139; 26.7%) and 73.3% (n = 382) had cN3 disease. Rate of axillary pCR was 34.2%, and breast and axillary pCR was 19.4% (n = 101). Event-free survival (EFS) at 5 years was 75.1% (95% CI, 0.71 to 0.79). Rate of locoregional recurrence was 6.7%; distant metastatic rate was 29.4%. Axillary pCR with or without breast pCR was significantly associated with longer EFS (p = 0.001). Achieving breast/axillary pCR was an independent predictor of improved EFS (hazard ratio 0.22, p < 0.0001). Having triple-negative disease was associated with worse EFS (hazard ratio 1.74, p = 0.008). CONCLUSIONS: In a high-risk cohort of patients with cN2-3 disease, trimodality therapy was effective in achieving durable EFS. Approximately one-third of patients achieved axillary pCR, which was associated with improved survival. Further studies are needed to accurately determine axillary response in cN2-3 breast cancer after NST in order to develop de-escalation strategies to reduce morbidity associated with axillary surgery.