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.

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.

Patient-reported outcomes in older breast cancer survivors with and without prior chemotherapy treatment.

BACKGROUND: Little is known about long-term treatment-related symptoms in older breast cancer survivors. We characterized long-term patient-reported symptoms and examined factors associated with the presence and severity of symptoms, and symptom interference with daily activities. METHODS: Texas Cancer Registry (TCR) Medicare linkage data was used to identify breast cancer patients age 65 and older with local/regional stage disease diagnosed between 2012-2013. Symptom burden was assessed using breast-specific items from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™). Demographic and clinical data also were collected. Logistic regression models were used to assess the association between symptom burden and respondent sociodemographic and clinical characteristics. RESULTS: Of 4448 eligible patients, 1594 (response-rate 35.8%) completed questionnaires. Of these, 1245 eligible respondents were included in the analysis based on self-reported data. Median time from diagnosis to survey completion was 68 months (IQR: 62-73). Most frequently reported symptoms were fatigue/lack of energy (76.8%), aching muscles (72.1%) and aching joints (72.5%). Receipt of chemotherapy was associated with higher symptom burden. Patients treated with adjuvant chemotherapy had higher risk of numbness/tingling (OR: 3.16; 95% CI: 2.36-4.24), hair loss (OR: 2.72; 95% CI: 2.05-3.60), and fatigue/lack of energy (OR: 1.80; 95% CI: 1.29-2.52). Similarly, patients who received chemotherapy were more likely to report the majority of symptoms as moderate to severe and as interfering with daily activities. CONCLUSION: Receipt of chemotherapy is associated with significant symptom burden more than 5 years after breast cancer treatment. Long-term chemotherapy impact should be discussed with patients in a shared-decision making process and approaches to symptom management during survivorship care are needed.

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.

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.

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.

Contemporary surgical management of inflammatory breast cancer: a narrative review.

OBJECTIVE: The purpose of this review is to outline the surgical management of inflammatory breast cancer (IBC) including the clinical decision making, operative approach and current controversies. BACKGROUND: IBC is a rare and aggressive form of breast cancer. Trimodality therapy consisting of neoadjuvant therapy, modified radical mastectomy (MRM) and radiation therapy improves survival and is the recommended course of treatment. Advancements in systemic therapy and de-escalation strategies in non-IBC have accelerated discussions regarding several aspects of care in IBC including feasibility of de-escalation of surgical care, timing of reconstruction and the role of surgery in de novo stage IV disease. We discuss the evidence to support the surgical approach and decision-making in this rare disease. METHODS: We reviewed existing literature using multiple electronic databases and clinical consensus guidelines to identify historical and current publications addressing current management recommendations and clinical controversies in IBC. CONCLUSIONS: Breast conserving surgery (BCS), skin- or nipple-sparing mastectomy should not be performed in IBC as surgical resection to negative margins results in improved locoregional recurrence rates. Level I and II axillary lymph node dissection should be performed regardless of response to therapy and initial nodal status. Reconstruction should be delayed and contralateral prophylactic mastectomy (CPM) is discouraged in IBC. Surgery may be considered for de novo stage IV IBC patients who demonstrate durable response to neoadjuvant therapy to improve local-regional control.

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.