Comparative analysis of the tumor microbiome, molecular profiles, and immune cell abundances by HPV status in mucosal head and neck cancers and their impact on survival.

Head and Neck Squamous Cell Carcinoma (HNSCC) comprises a diverse group of tumors with variable treatment response and prognosis. The tumor microenvironment (TME), which includes microbiome and immune cells, can impact outcomes. Here, we sought to relate the presence of specific microbes, gene expression, and tumor immune infiltration using tumor transcriptomics from The Cancer Genome Atlas (TCGA) and associate these with overall survival (OS). RNA sequencing (RNAseq) from HNSCC tumors in TCGA was processed through the exogenous sequences in tumors and immune cells (exotic) pipeline to identify and quantify low-abundance microbes. The detection of the Papillomaviridae family of viruses assessed HPV status. All statistical analyses were performed using R. A total of 499 RNAseq samples from TCGA were analyzed. HPV was detected in 111 samples (22%), most commonly Alphapapillomavirus 9 (90.1%). The presence of Alphapapillomavirus 9 was associated with improved OS [HR = 0.60 (95%CI: 0.40-0.89, p = .01)]. Among other microbes, Yersinia pseudotuberculosis was associated with the worst survival (HR = 3.88; p = .008), while Pseudomonas viridiflava had the best survival (HR = 0.05; p = .036). Microbial species found more abundant in HPV- tumors included several gram-negative anaerobes. HPV- tumors had a significantly higher abundance of M0 (p < .001) and M2 macrophages (p = .035), while HPV+ tumors had more T regulatory cells (p < .001) and CD8+ T-cells (p < .001). We identified microbes in HNSCC tumor samples significantly associated with survival. A greater abundance of certain anaerobic microbes was seen in HPV tumors and pro-tumorigenic macrophages. These findings suggest that TME can be used to predict patient outcomes and may help identify mechanisms of resistance to systemic therapies.

Axillary Management: How Much Is Too Much?

PURPOSE OF REVIEW: To review the current management of the axilla in breast cancer. RECENT FINDINGS: Axillary dissection is no longer indicated in patients with clinically node-negative axilla with 1-2 positive sentinel lymph nodes following upfront surgery or in patients with clinically node-negative axilla following neoadjuvant chemotherapy. Breast cancer has evolved away from routine axillary clearance to the less invasive sentinel lymph node biopsy to now complete omission of axillary sampling in select patients. We will review the most salient evidence that has shaped these practice changes over the last three decades. Current practice controversies are especially relevant for elderly populations and those receiving neoadjuvant therapy. Ongoing clinical trials will provide data to further guide breast cancer surgical management.

Palliative Quad Shot Radiation Therapy with or without Concurrent Immune Checkpoint Inhibition for Head and Neck Cancer.

OBJECTIVES: Patients with recurrent and metastatic head and neck cancer (HNC) have limited treatment options. 'QuadShot' (QS), a hypofractionated palliative radiotherapy regimen, can provide symptomatic relief and local control and may potentiate the effects of immune checkpoint inhibitors (ICIs). We compared outcomes of QS ± concurrent ICIs in the palliative treatment of HNC. MATERIALS AND METHODS: We identified patients who received ≥three cycles of QS from 2017 to 2022 and excluded patients without post-treatment clinical evaluation or imaging. Outcomes for patients who received QS alone were compared to those treated with ICI concurrent with QS, defined as receipt of ICI within 4 weeks of QS. RESULTS: Seventy patients were included, of whom 57% received concurrent ICI. Median age was 65.5 years (interquartile range [IQR]: 57.9-77.8), and 50% patients had received prior radiation to a median dose of 66 Gy (IQR: 60-70). Median follow-up was 8.8 months. Local control was significantly higher with concurrent ICIs (12-month: 85% vs. 63%, p = 0.038). Distant control (12-month: 56% vs. 63%, p = 0.629) and median overall survival (9.0 vs. 10.0 months, p = 0.850) were similar between the two groups. On multivariable analysis, concurrent ICI was a significant predictor of local control (HR for local failure: 0.238; 95% CI: 0.073-0.778; p = 0.018). Overall, 23% patients experienced grade 3 toxicities, which was similar between the two groups. CONCLUSIONS: The combination of QS with concurrent ICIs was well tolerated and significantly improved local control compared to QS alone. The median OS of 9.4 months compares favorably to historical controls for patients with HNC treated with QS. This approach represents a promising treatment option for patients with HNC unsuited for curative-intent treatment and warrants prospective evaluation.

Immunoprofiles and Oncologic Outcomes of 15 Patients with Androgen Receptor-Positive Salivary Duct Carcinoma.

BACKGROUND: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. METHODS: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan-Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). RESULTS: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8-6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. CONCLUSION: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients.

Scalp Irradiation with 3D-Milled Bolus: Initial Dosimetric and Clinical Experience.

BACKGROUND AND PURPOSE: A bolus is required when treating scalp lesions with photon radiation therapy. Traditional bolus materials face several issues, including air gaps and setup difficulty due to irregular, convex scalp geometry. A 3D-milled bolus is custom-formed to match individual patient anatomy, allowing improved dose coverage and homogeneity. Here, we describe the creation process of a 3D-milled bolus and report the outcomes for patients with scalp malignancies treated with Volumetric Modulated Arc Therapy (VMAT) utilizing a 3D-milled bolus. MATERIALS AND METHODS: Twenty-two patients treated from 2016 to 2022 using a 3D-milled bolus and VMAT were included. Histologies included squamous cell carcinoma (n = 14, 64%) and angiosarcoma (n = 8, 36%). A total of 7 (32%) patients were treated in the intact and 15 (68%) in the postoperative setting. The median prescription dose was 66.0 Gy (range: 60.0-69.96). RESULTS: The target included the entire scalp for 8 (36%) patients; in the remaining 14 (64%), the median ratio of planning target volume to scalp volume was 35% (range: 25-90%). The median dose homogeneity index was 1.07 (range: 1.03-1.15). Six (27%) patients experienced acute grade 3 dermatitis and one (5%) patient experienced late grade 3 skin ulceration. With a median follow-up of 21.4 months (range: 4.0-75.4), the 18-month rates of locoregional control and overall survival were 75% and 79%, respectively. CONCLUSIONS: To our knowledge, this is the first study to report the clinical outcomes for patients with scalp malignancies treated with the combination of VMAT and a 3D-milled bolus. This technique resulted in favorable clinical outcomes and an acceptable toxicity profile in comparison with historic controls and warrants further investigation in a larger prospective study.

Prognosis of South Asian Buccal Mucosa Cancer Patients in the United States: Association of Race with Overall Survival.

BACKGROUND: Squamous Cell Carcinoma (SCC) of the buccal mucosa and gingiva accounts for approximately 10% of oral and pharyngeal cancers diagnosed in the United States each year, with a disproportionally higher incidence in individuals of South Asian descent. However, little has been documented regarding trends pertaining to overall survival. Thus, this research serves to identify predictors of survival and determine if overall survival (OS) differs for South Asians compared to other races once they develop non-metastatic buccal mucosa or gingiva squamous cell carcinoma. METHODS: A population-based, cohort study of patients registered in the National Cancer Database® (NCDB) between the years 2004-2016 was performed. Kaplan-Meyer Survival Curves were executed to examine overall survival, while univariable (UVA) and multivariable analysis (MVA) was performed to determine the effect of multiple variables on OS. RESULTS: South Asians had longer median OS at 88.7 months, compared to 58.6 months and 38.3 months for Caucasians and African Americans respectively (p<0.001). In UVA, race was highly significant, but when the cohort was selected to include only those who had undergone surgical resection, no statistically significant difference remained. On MVA, lack of surgery, older age, higher grade, higher T and N stage, use of chemotherapy, higher comorbidity scores were associated with worse OS, but race was not significant. CONCLUSION: South Asians in the US with non-metastatic buccal mucosa or gingiva SCC have better OS compared to Caucasians or African Americans, likely due to younger age at diagnosis (median 59 vs. 71 and 62 years old) and more frequent surgical resection (75% vs. 72% and 64%). In MVA, South Asians have similar OS as Caucasians.

A Multicenter Evaluation of Different Chemotherapy Regimens in Older Adults With Head and Neck Squamous Cell Carcinoma Undergoing Definitive Chemoradiation.

PURPOSE: The number of older adults with head and neck squamous cell carcinoma (HNSCC) is increasing, and treatment of these patients is challenging. Although cisplatin-based chemotherapy concomitantly with radiation therapy is considered the standard regimen for patients with locoregionally advanced HNSCC, there is substantial real-world heterogeneity regarding concomitant chemotherapy in older patients with HNSCC. METHODS AND MATERIALS: The SENIOR study is an international multicenter cohort study including older patients (≥65 years) with HNSCC treated with definitive radiation therapy at 13 academic centers in the United States and Europe. Patients with concomitant chemoradiation were analyzed regarding overall survival (OS) and progression-free survival (PFS) via Kaplan-Meier analyses. Fine-Gray competing risk regressions were performed regarding the incidence of locoregional failures and distant metastases. RESULTS: Six hundred ninety-seven patients with a median age of 71 years were included in this analysis. Single-agent cisplatin was the most common chemotherapy regimen (n = 310; 44%), followed by cisplatin plus 5-fluorouracil (n = 137; 20%), carboplatin (n = 73; 10%), and mitomycin C plus 5-fluorouracil (n = 64; 9%). Carboplatin-based regimens were associated with diminished PFS (hazard ratio [HR], 1.39 [1.03-1.89]; P < .05) and a higher incidence of locoregional failures (subdistribution HR, 1.54 [1.00-2.38]; P = .05) compared with single-agent cisplatin, whereas OS (HR, 1.15 [0.80-1.65]; P = .46) was comparable. There were no oncological differences between single-agent and multiagent cisplatin regimens (all P > .05). The median cumulative dose of cisplatin was 180 mg/m2 (IQR, 120-200 mg/m2). Cumulative cisplatin doses ≥200 mg/m2 were associated with increased OS (HR, 0.71 [0.53-0.95]; P = .02), increased PFS (HR, 0.66 [0.51-0.87]; P = .003), and lower incidence of locoregional failures (subdistribution HR, 0.50 [0.31-0.80]; P = .004). Higher cumulative cisplatin doses remained an independent prognostic variable in the multivariate regression analysis for OS (HR, 0.996 [0.993-0.999]; P = .009). CONCLUSIONS: Single-agent cisplatin can be considered in the standard chemotherapy regimen for older patients with HNSCC who can tolerate cisplatin. Cumulative cisplatin doses are prognostically relevant in older patients with HNSCC.

Factors Associated with Total Laryngectomy Utilization in Patients with cT4a Laryngeal Cancer.

BACKGROUND: Despite recommendations for upfront total laryngectomy (TL), many patients with cT4a laryngeal cancer (LC) instead undergo definitive chemoradiation, which is associated with inferior survival. Sociodemographic and oncologic characteristics associated with TL utilization in this population are understudied. METHODS: This retrospective cohort study utilized hospital registry data from the National Cancer Database to analyze patients diagnosed with cT4a LC from 2004 to 2017. Patients were stratified by receipt of TL, and patient and facility characteristics were compared between the two groups. Logistic regression analyses and Cox proportional hazards methodology were performed to determine variables associated with receipt of TL and with overall survival (OS), respectively. OS was estimated using the Kaplan-Meier method and compared between treatment groups using log-rank testing. TL usage over time was assessed. RESULTS: There were 11,149 patients identified. TL utilization increased from 36% in 2004 to 55% in 2017. Treatment at an academic/research program (OR 3.06) or integrated network cancer program (OR 1.50), male sex (OR 1.19), and Medicaid insurance (OR 1.31) were associated with increased likelihood of undergoing TL on multivariate analysis (MVA), whereas age > 61 (OR 0.81), Charlson-Deyo comorbidity score ≥ 3 (OR 0.74), and clinically positive regional nodes (OR 0.78 [cN1], OR 0.67 [cN2], OR 0.21 [cN3]) were associated with decreased likelihood. Those undergoing TL with post-operative radiotherapy (+/- chemotherapy) had better survival than those receiving chemoradiation (median OS 121 vs. 97 months; p = 0.003), and TL + PORT was associated with lower risk of death compared to chemoradiation on MVA (HR 0.72; p = 0.024). CONCLUSIONS: Usage of TL for cT4a LC is increasing over time but remains below 60%. Patients seeking care at academic/research centers are significantly more likely to undergo TL, highlighting the importance of decreasing barriers to accessing these centers. Increased focus should be placed on understanding and addressing the additional patient-, physician-, and system-level factors that lead to decreased utilization of surgery.

Clinical characteristics, racial inequities, and outcomes in patients with breast cancer and COVID-19: A COVID-19 and cancer consortium (CCC19) cohort study.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. Clinical trial number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

Survival outcomes seen with neoadjuvant chemotherapy in the management of locally advanced inflammatory breast cancer (IBC) versus matched controls.

Inflammatory breast cancer (IBC) poses an ongoing challenge as rates of disease recurrence and mortality remain high compared to stage-matched controls. However, frontline therapy has evolved through the years, including the widespread use of neoadjuvant chemotherapy (NAC) given the prognostic importance of pathologic complete response (pCR). Due to these sweeping changes, we need new data to assess current recurrence and survival outcomes for locally advanced IBC in the context of matched non-inflammatory controls. We conducted a retrospective analysis of institutional IBC data from 2010 to 2016 with the primary objective of comparing overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS). We matched IBC patients to non-inflammatory controls based on age, receptor status, tumor grade, clinical stage, and receipt of prior NAC. Secondary objectives included assessing pCR rates and identifying prognostic factors. Among NAC recipients, we observed similar pCR rates (47.6 % vs. 49.4 %, p = 0.88) between IBC (n = 84) and matched non-IBC (n = 81) cohorts. However, we noted a significant worsening of OS (p = 0.0001), RFS (p = 0.0001), and DRFS (p = 0.001) in the IBC group. Specifically, 5-year OS in the IBC cohort was 58.9 % vs. 86.7 % for matched controls (p = 0.0003). Older age was a weak negative predictor for OS (HR 1.03, p = 0.001) and RFS (HR 1.02, p = 0.01). For DRFS, older age was also a weak negative predictor (HR 1.02, p = 0.02), whereas the use of NAC was a positive predictor (HR 0.47, p = 0.02). Despite no clear difference in pCR, survival outcomes remain poor for IBC compared to matched non-inflammatory controls.

Deep Learning Architecture to Improve Edge Accuracy of Auto-Contouring for Head and Neck Radiotherapy.

Deep learning (DL) methods have shown great promise in auto-segmentation problems. However, for head and neck cancer, we show that DL methods fail at the axial edges of the gross tumor volume (GTV) where the segmentation is dependent on information closer to the center of the tumor. These failures may decrease trust and usage of proposed auto-contouring systems. To increase performance at the axial edges, we propose the spatially adjusted recurrent convolution U-Net (SARC U-Net). Our method uses convolutional recurrent neural networks and spatial transformer networks to push information from salient regions out to the axial edges. On average, our model increased the Sørensen-Dice coefficient (DSC) at the axial edges of the GTV by 11% inferiorly and 19.3% superiorly over a baseline 2D U-Net, which has no inherent way to capture information between adjacent slices. Over all slices, our proposed architecture achieved a DSC of 0.613, whereas a 3D and 2D U-Net achieved a DSC of 0.586 and 0.540, respectively. SARC U-Net can increase accuracy at the axial edges of GTV contours while also increasing accuracy over baseline models, creating a more robust contour.

Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD-1-refractory cancer.

BACKGROUND: Immunotherapies are becoming front-line treatments for many advanced cancers, and combinations of two or more therapies are beginning to be investigated. Based on their individual antitumor capabilities, we sought to determine whether combination oncolytic virus (OV) and radiation therapy (RT) may improve cancer outcomes. METHODS: To investigate the activity of this combination therapy, we used in vitro mouse and human cancer cell lines as well as a mouse model of skin cancer. After initial results, we further included immune checkpoint blockade, whose addition constituted a triple combination immunotherapy. RESULTS: Our findings demonstrate that OV and RT reduce tumor growth via conversion of immunologically 'cold' tumors to 'hot', via a CD8+ T cell-dependent and IL-1α-dependent mechanism that is associated with increased PD-1/PD-L1 expression, and the triple combination of OV, RT, and PD-1 checkpoint inhibition impedes tumor growth and prolongs survival. Further, we describe the response of a PD-1-refractory patient with cutaneous squamous cell carcinoma who received the triple combination of OV, RT, and immune checkpoint inhibitor (ICI), and went on to experience unexpected, prolonged control and survival. He remains off-treatment and is without evidence of progression for >44 months since study entry. CONCLUSIONS: Effective systemic antitumor immune response is rarely elicited by a single therapy. In a skin cancer mouse model, we demonstrate improved outcomes with combination OV, RT, and ICI treatment, which is associated with mechanisms involving augmented CD8+ T cell infiltration and IL-1α expression. We report tumor reduction and prolonged survival of a patient with skin cancer treated with combination OV, RT, and ICI. Overall, our data provide strong rationale for combining OV, RT, and ICI for treatment of patients with ICI-refractory skin and potentially other cancers.

Implementation of a Breast Intraoperative Oncoplastic Form to Aid Management of Oncoplastic Surgery.

INTRODUCTION: Oncoplastic breast conservation surgery (BCS) uses concurrent reduction and/or mastopexy with lumpectomy to improve aesthetic outcomes. However, tissue rearrangement can shift the original tumor location site in relation to external breast landmarks, resulting in difficulties during re-excision for a positive margin and accurate radiation targeting. We developed the Breast Intraoperative Oncoplastic (BIO) form to help depict the location of the tumor and breast reduction specimen. This study seeks to assess physician perspectives of the implementation outcomes. METHODS: From February 2021 to April 2021, the BIO form was used in 11 oncoplastic BCS cases at a single institution. With institutional review board approval, surgical oncologists (SOs), plastic surgeons (PSs), and radiation oncologists (ROs) were administered a 12-question validated survey on Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM), using a 5-point Likert scale during initial implementation and at 6-month reassessment. RESULTS: Twelve physicians completed the survey initially (4 SOs, 4 PSs, and 4 ROs). The mean scores for Acceptability of Intervention Measure, Intervention Appropriateness Measure, and Feasibility of Intervention Measure were high (4.44, 4.56, and 4.56, respectively). Twelve completed the second survey (5 SOs, 3 PSs, and 4 ROs). The mean scores were marginally lower (4.06, 4.21, and 4.25). There were no significant differences when stratified by number of years in practice or specialty. Free text comments showed that 75% of physicians found the form helpful in oncoplastic BCS. CONCLUSIONS: The data indicate high feasibility, acceptability, and appropriateness of the BIO form. Results of this study suggest multidisciplinary benefits of implementing the BIO form in oncoplastic BCS.

Clinical Characteristics, Racial Inequities, and Outcomes in Patients with Breast Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Cohort Study.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1,383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32 - 1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70 - 6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83 - 12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63 - 3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20 - 2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66 - 3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89 - 22.6]). Hispanic ethnicity, timing and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to Non-Hispanic White patients.

The Axillary Lateral Vessel Thoracic Junction Is Not an Organ at Risk for Breast Cancer-Related Lymphedema.

PURPOSE: Breast cancer-related lymphedema (BCRL) is a treatment complication that significantly reduces patient quality of life. Regional nodal irradiation (RNI) may increase the risk of BCRL. Recently, a region of the axilla known as the axillary-lateral thoracic vessel juncture (ALTJ) was identified as a potential organ at risk (OAR). Here, we set out to validate whether radiation dose to the ALTJ is associated with BCRL. METHODS AND MATERIALS: We identified patients with stage II-III breast cancer treated with adjuvant RNI from 2013 to 2018, excluding those with BCRL preradiation. We defined BCRL as difference in arm circumference between the ipsilateral and contralateral limb >2.5 cm at any 1 encounter or ≥2 cm on ≥2 visits. All patients suspected of having BCRL at routine follow-up visits were referred to physical therapy for confirmation. The ALTJ was retrospectively contoured and dose metrics were collected. Cox proportional hazards regression models were used to test the association between clinical and dosimetric parameters with the development of BCRL. RESULTS: The study population included 378 patients with a median age of 53 years, median body mass index of 28.4 kg/m2, and median of 18 axillary nodes removed; 71% underwent mastectomy. Median follow-up was 70 months (interquartile range, 55-89.7 months). BCRL developed in 101 patients at a median of 18.9 months (interquartile range, 9.9-32.4 months), with a corresponding 5-year cumulative incidence BCRL of 25.8%. On multivariate analysis, none of the ALTJ metrics were associated with BCRL risk. Only increasing age, increasing body mass index, and increasing number of nodes were associated with a higher risk of developing BCRL. The 6-year locoregional recurrence rate was 3.2%, the axillary recurrence rate was 1.7%, and the isolated axillary recurrence rate was 0%. CONCLUSIONS: The ALTJ is not validated as a critical OAR for reducing BCRL risk. Until such an OAR is discovered, the axillary PTV should not be modified or dose reduced in efforts to reduce BCRL.

Disparities in Survival Outcomes among Racial/Ethnic Minorities with Head and Neck Squamous Cell Cancer in the United States.

BACKGROUND: Racial/ethnic (R/E) minorities with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes compared to White patients. While disparities in patient outcomes for R/E minorities have been well documented, the specific drivers of the inferior outcomes remain poorly understood. PATIENTS AND METHODS: This was a population-based retrospective cohort study that analyzed HNSCC patients using the National Cancer Database (NCDB) from 2000-2016. Patient outcomes were stratified by R/E groups including White, Black, Hispanic, Native American/Other, and Asian. The main outcome in this study was overall survival (OS). Univariate time-to-event survival analyses were performed using the Kaplan-Meier product limit estimates and the log-rank test to evaluate the differences between strata. RESULTS: There were 304,138 patients with HNSCC identified in this study, of which 262,762 (86.3%) were White, 32,528 (10.6%) were Black, 6191 were Asian (2.0%), and 2657 were Native American/Other (0.9%). Black R/E minorities were more likely to be uninsured (9% vs. 5%, p < 0.0001), have Medicaid insurance (22% vs. 8%, p < 0.0001), be in a lower income quartile (<30,000, 42% vs. 13%, p < 0.0001), have metastatic disease (5% vs. 2%, p < 0.001), and have a total treatment time 6 days longer than White patients (median 107 vs. 101 days, p < 0.001). The 5-year OS for White, Black, Native American/Other, and Asian patients was 50.8%, 38.6%, 51.1%, and 55.8%, respectively. Among the oropharynx HNSCC patients, the 5-year OS rates in p16+ White, Black, and Asian patients were 65.7%, 39.4%%, and 55%, respectively. After a multivariate analysis, Black race was still associated with an inferior OS (HR:1.09, 95% CI: 1.03-1.15, p = 0.002). CONCLUSIONS: This large cohort study of HNSCC patients demonstrates that Black race is independently associated with worse OS, in part due to socioeconomic, clinical, and treatment-related factors.

Prostate brachytherapy utilization in the COVID-19 era: A cross-sectional study of radiation oncologists in the United States.

PURPOSE: Despite advantages such as abbreviated treatment course, brachytherapy (BT) utilization rates for prostate cancer (PC) in the United States (US) are declining. We surveyed practicing US radiation oncologists (ROs) to determine the proportion who offer BT for PC and whether the COVID-19 pandemic influenced practice patterns. MATERIALS AND METHODS: From July-October 2021, we surveyed practicing US ROs. Provider demographic and practice characteristics were collected. Questions assessing utilization of BT and external beam (EBRT) for patients of varying risk groups and the effect of the pandemic on practice patterns were administered. Descriptive statistics were reported. The bivariate relationships between provider characteristics and likelihood of offering BT were assessed using the Chi-square test (α < 0.05). RESULTS: Six percent of surveyed ROs responded, with 203 meeting inclusion criteria (72% male, 72% white, 53% non-academic, 69% >10 years in practice) and 156 (77%) treating PC. For low-risk, fewer providers offered BT (41% total; 25% low dose rate [LDR], 10% high dose rate [HDR], 6% both) than stereotactic body (SBRT) (54%) and moderately hypofractionated radiation therapy (MHFRT) (83%). For favorable intermediate risk, fewer offered BT (37% total; 21% LDR, 10% HDR, 6% both) than SBRT (48%), MHFRT (87%), and conventionally fractionated EBRT (38%). For high (44%) and very-high (37%) risk, fewer offered EBRT+BT than EBRT alone. For every risk group, academic ROs were significantly more likely to offer BT (all p-values<0.05). <1% of respondents reported increased pandemic-related BT usage. CONCLUSIONS: US ROs, particularly in non-academic settings, do not routinely offer BT monotherapy or boost (<50%). Practice patterns were unaffected by COVID-19. Retraining may be critical to increasing utilization.

Astragaloside IV enhances the sensitivity of breast cancer stem cells to paclitaxel by inhibiting stemness.

Background: Chemotherapy is one of the common treatments for breast cancer. The induction of cancer stem cells (CSCs) is an important reason for chemotherapy failure and breast cancer recurrence. Astragaloside IV (ASIV) is one of the effective components of the traditional Chinese medicine (TCM) Astragalus membranaceus, which can improve the sensitivity of various tumors to chemotherapy drugs. Here, we explored the sensitization effect of ASIV to chemotherapy drug paclitaxel (PTX) in breast cancer from the perspective of CSCs. Methods: The study included both in vitro and in vivo experiments. CSCs from the breast cancer cell line MCF7 with stem cell characteristics were successfully induced in vitro. Cell viability and proliferation were detected using the Cell Counting Kit-8 (CCK-8) and colony formation assays, and flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) methods were performed to detect cell apoptosis. Stemness-related protein expression was determined by western blotting (WB) and immunohistochemistry (IHC). Body weight, histopathology, and visceral organ damage of mice were used to monitor drug toxicity. Results: The expression of stemness markers including Sox2, Nanog, and ALDHA1 was stronger in MCF7-CSCs than in MCF7. PTX treatment inhibited the proliferation of tumor cells by promoting cell apoptosis, whereas the stemness of breast cancer stem cells (BCSCs) resisted the effects of PTX. ASIV decreased the stemness of BCSCs, increased the sensitivity of BCSCs to PTX, and synergistically promoted PTX-induced apoptosis of breast cancer cells. Our results showed that the total cell apoptosis rate increased by about 25% after adding ASIV compared with BCSCs treated with PTX alone. The in vivo experiments demonstrated that ASIV enhanced the ability of PTX to inhibit the growth of breast cancer. WB and IHC showed that ASIV reduced the stemness of CSCs. Conclusions: In this study, the resistance of breast cancer to PTX was attributed to the existence of CSCs; ASIV weakened the resistance of MCF7-CSCs to PTX by significantly attenuating the hallmarks of breast cancer stemness and improved the efficacy of PTX.

Stereotactic Radiosurgery for Women Older than 65 with Breast Cancer Brain Metastases.

BACKGROUND: Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of older breast cancer patients ≥65 years old with BM compared to younger patients at our institution. METHODS: An IRB-approved single-institutional retrospective review of biopsy-proven breast cancer patients with BM treated with 1- to 5-fraction stereotactic radiation therapy (SRS) from 2015 to 2020 was performed. Primary endpoint was intracranial progression-free survival (PFS) defined as the time interval between the end of SRS to the date of the first CNS progression. Secondary endpoints were overall survival (OS) from the end of SRS and radiation treatment patterns. Kaplan-Meier estimates and Cox proportional hazard regression method were used for survival analyses. RESULTS: A total of 112 metastatic breast cancer patients with BMs were included of which 24 were ≥65 years old and 88 were <65 years old. Median age at RT was 72 years (range 65-84) compared to 52 years (31-64) in younger patients. There were significantly higher number of older women with ER/PR positive disease (75% vs. 49%, p = 0.036), while younger patients were more frequently triple negative (32% vs. 12%, p = 0.074) and HER2 positive (42% vs. 29%, p = 0.3). Treatment-related adverse events were similar in both groups. Overall, 14.3% patients had any grade radiation necrosis (RN) (older vs. young: 8.3% vs. 16%, p = 0.5) while 5.4% had grade 3 or higher RN (0% vs. 6.8%, p = 0.7). Median OS after RT was poorer in older patients compared to younger patients (9.5 months vs. 14.5 months, p = 0.037), while intracranial PFS from RT was similar between the two groups (9.7 months vs. 7.1 months, p = 0.580). On univariate analysis, significant predictors of OS were age ≥65 years old (hazard risk, HR = 1.70, p = 0.048), KPS ≤ 80 (HR = 2.24, p < 0.001), HER2 positive disease (HR = 0.46, p < 0.001), isolated CNS metastatic disease (HR = 0.29, p < 0.001), number of brain metastases treated with RT (HR = 1.06, p = 0.028), and fractionated SRS (HR = 0.53, p = 0.013). On multivariable analysis, KPS ≤ 80, HER2 negativity and higher number of brain metastases predicted for poorer survival, while age was not a significant factor for OS after adjusting for other variables. Patients who received systemic therapy after SRS had a significantly improved OS on univariate and multivariable analysis (HR = 0.32, p < 0.001). Number of brain metastases treated was the only factor predictive of worse PFS (HR = 1.06, p = 0.041), which implies a 6% additive risk of progression for every additional metastasis treated. CONCLUSIONS: Although older women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression, and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths, and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and that outcomes for breast cancer patients with BMs and personalized decision-making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in older patients.