A national quality improvement study identifying and addressing cancer screening deficits due to the COVID-19 pandemic.

BACKGROUND: Cancer-related deaths over the next decade are expected to increase due to cancer screening deficits associated with the coronavirus disease 2019 (COVID-19) pandemic. Although national deficits have been quantified, a structured response to identifying and addressing local deficits has not been widely available. The objectives of this report are to share preliminary data on monthly screening deficits in breast, colorectal, lung, and cervical cancers across diverse settings and to provide online materials from a national quality improvement (QI) study to help other institutions to address local screening deficits. METHODS: This prospective, national QI study on Return-to-Screening enrolled 748 accredited cancer programs in the United States from April through June 2021. Local prepandemic and pandemic monthly screening test volumes (MTVs) were used to calculate the relative percent change in MTV to describe the monthly screening gap. RESULTS: The majority of facilities reported monthly screening deficits (colorectal cancer, 80.6% [n = 104/129]; cervical cancer, 69.0% [n = 20/29]; breast cancer, 55.3% [n = 241/436]; lung cancer, 44.6% [n = 98/220]). Overall, the median relative percent change in MTV ranged from -17.7% for colorectal cancer (interquartile range [IQR], -33.6% to -2.8%), -6.8% for cervical cancer (IQR, -29.4% to 1.7%), -1.6% for breast cancer (IQR, -9.6% to 7.0%), and 1.2% for lung cancer (IQR, -16.9% to 19.0%). Geographic differences were not observed. There were statistically significant differences in the percent change in MTV between institution types for colorectal cancer screening (P = .02). CONCLUSION: Cancer screening is still in need of urgent attention, and the screening resources made available online may help facilities to close critical gaps and address screenings missed in 2020. LAY SUMMARY: Question: How can the effects of the coronavirus disease 2019 pandemic on cancer screening be mitigated? FINDINGS: When national resources were provided, including methods to calculate local screening deficits, 748 cancer programs promptly enrolled in a national Return-to-Screening study, and the majority identified local screening deficits, most notably in colorectal cancer. Using these results, 814 quality improvement projects were initiated with the potential to add 70,000 screening tests in 2021. Meaning: Cancer screening is still in need of urgent attention, and the online resources that we provide may help to close critical screening deficits.

The Impact of Radiotherapy Delay in Breast Conservation Patients Not Receiving Chemotherapy and the Rationale for Dichotomizing the Radiation Oncology Time-Dependent Standard into Two Quality Measures.

INTRODUCTION: The Commission on Cancer/National Quality Forum breast radiotherapy quality measure establishes that for women < 70 years, adjuvant radiotherapy after breast conserving surgery (BCS) should be started < 1 year from diagnosis. This was intended to prevent accidental radiotherapy omission or delay due to a long interval between surgery and chemotherapy completion, when radiation is delivered. However, the impact on patients not receiving chemotherapy, who proceed from surgery directly to radiotherapy, remains unknown. PATIENTS AND METHODS: Patients aged 18-69, diagnosed with stage I-III breast cancer as their first and only cancer diagnosis (2004-2016), having BCS, for whom this measure would be applicable, were reviewed from the National Cancer Database. RESULTS: Among 308,521 patients, the median age was 57.0 years, and > 99% of all patients were compliant with the measure. The cohort of interest included 186,650 (60.5%) patients not receiving chemotherapy, with a mean age of 57.9 years. Of these, 90.5% received external beam radiotherapy (EBRT) and 9.5% brachytherapy. Among them, 24.9% started radiotherapy > 8 weeks after surgery. In a multivariable model, delay from surgery to radiotherapy increased the hazard ratios for overall survival to 9.0% (EBRT) per month and 3.0% (brachytherapy) per week. CONCLUSION: While 99.9% of patients undergoing BCS without chemotherapy remain compliant with the current quality measure, 25% have delays > 8 weeks to start radiation, which is associated with impaired survival. These data suggest that the current quality measure should be dichotomized into two, with or without chemotherapy, in order to impel prompt radiotherapy initiation and maximize outcomes in all patients.

Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. the COVID-19 pandemic breast cancer consortium.

The COVID-19 pandemic presents clinicians a unique set of challenges in managing breast cancer (BC) patients. As hospital resources and staff become more limited during the COVID-19 pandemic, it becomes critically important to define which BC patients require more urgent care and which patients can wait for treatment until the pandemic is over. In this Special Communication, we use expert opinion of representatives from multiple cancer care organizations to categorize BC patients into priority levels (A, B, C) for urgency of care across all specialties. Additionally, we provide treatment recommendations for each of these patient scenarios. Priority A patients have conditions that are immediately life threatening or symptomatic requiring urgent treatment. Priority B patients have conditions that do not require immediate treatment but should start treatment before the pandemic is over. Priority C patients have conditions that can be safely deferred until the pandemic is over. The implementation of these recommendations for patient triage, which are based on the highest level available evidence, must be adapted to current availability of hospital resources and severity of the COVID-19 pandemic in each region of the country. Additionally, the risk of disease progression and worse outcomes for patients need to be weighed against the risk of patient and staff exposure to SARS CoV-2 (virus associated with the COVID-19 pandemic). Physicians should use these recommendations to prioritize care for their BC patients and adapt treatment recommendations to the local context at their hospital.

Physician Knowledge of Breast Cancer Recurrence and Contralateral Breast Cancer Risk is Associated with Increased Recommendations for Contralateral Prophylactic Mastectomy: a Survey of Physicians at NAPBC-Accredited Centers.

BACKGROUND: Physician recommendation for contralateral prophylactic mastectomy (CPM) has been shown to influence whether a patient chooses CPM. Few studies have explored physician knowledge about contralateral breast cancer (CBC) and local recurrence (LR) risk and whether knowledge is associated with recommendation for CPM. METHODS: We conducted a cross-sectional survey of physicians at National Accreditation Program for Breast Centers-accredited breast centers across the USA. Physician knowledge levels of CBC and LR were assessed and correlated with recommendations for CPM. RESULTS: A total of 2412 physicians were surveyed with a 51% response rate (n = 1226). The results showed that 66% had correct knowledge about CBC risk and 57% had correct knowledge about LR. Moreover, 634 had high knowledge, viz. 176 (55.4%) breast surgeons, 171 (58.0%) medical oncologists, 196 (62.0%) radiation oncologists, and 72 (29.9%) plastic surgeons (p < 0.01). Compared with high knowledge, low knowledge was associated with favoring insurance coverage for patients at average CBC risk (53.8% vs. 39.8%, p < 0.01). Low knowledge was also associated with feeling that CPM was indicated in patients with high recurrence anxiety (39.2% vs. 28.9%), young patients with estrogen receptor (ER)-negative cancer (25.3% vs. 18.5%), and patients with two first-degree relatives with breast cancer (40.0% vs. 32.3%) (all p < 0.01). Multivariable analysis found physician type [odds ratio (OR) 3.76 for surgeons] and low knowledge (OR 1.46) to be significant independent predictors of favoring insurance coverage for CPM in patients at average risk. CONCLUSIONS: Physician knowledge about CBC and LR could be improved. Lower knowledge is associated with favorable physician recommendations for CPM. It is not clear whether improving physician knowledge will change recommendations for CPM.

Impact of Breast Center Accreditation on Compliance with Breast Quality Performance Measures at Commission on Cancer-Accredited Centers.

PURPOSE: This study was designed to determine whether accreditation by the National Accreditation Program for Breast Centers (NAPBC) is associated with improved performance on six breast quality measures pertaining to adjuvant treatment, needle/core biopsy, and breast conservation therapy rates at Commission on Cancer (CoC) centers. METHODS: National Cancer Database 2015 data were retrospectively reviewed to compare patients treated at CoC centers with and without NAPBC accreditation for compliance on six breast cancer quality measures. Mixed effects modeling determined performance on the quality measures adjusting for patient, tumor, and facility factors. RESULTS: Of 1308 CoC facilities, 484 (37%) were NAPBC-accredited and 111,547 patients (48%) were treated at NAPBC centers. More than 80% of patients treated at both NAPBC and non-NAPBC centers received care in compliance with breast quality measures. NAPBC centers achieved significantly higher performance on four of the five quality measures than non-NAPBC centers at the patient level and on five of six measures at the facility level. For two measures, needle/core biopsy before surgical treatment of breast cancer and breast conservation therapy rate of 50%, NAPBC centers were twice as likely as non-NAPBC centers to perform at the level expected by the CoC (respectively odds ratio [OR] 1.96, 95% confidence interval [CI] 1.85-2.08, p < 0.0001; and OR 2.05, 95% CI 1.94-2.15, p < 0.0001). CONCLUSIONS: While NAPBC accreditation at CoC centers is associated with higher performance on breast quality measures, the majority of patients at all centers receive guideline-concordant care. Future studies will determine whether higher performance translates into improved oncologic and patient-reported outcomes.

Germline Genetic Testing: What the Breast Surgeon Needs to Know.

PURPOSE: The American Society of Breast Surgeons (ASBrS) sought to provide educational guidelines for breast surgeons on how to incorporate genetic information and genomics into their practice. METHODS: A comprehensive nonsystematic review was performed of selected peer-reviewed literature. The Genetics Working Group of the ASBrS convened to develop guideline recommendations. RESULTS: Clinical and educational guidelines were prepared to outline the essential knowledge for breast surgeons to perform germline genetic testing and to incorporate the findings into their practice, which have been approved by the ASBrS Board of Directors. RECOMMENDATIONS: Thousands of women in the USA would potentially benefit from genetic testing for BRCA1, BRCA2, and other breast cancer genes that markedly increase their risk of developing breast cancer. As genetic testing is now becoming more widely available, women should be made aware of these tests and consider testing. Breast surgeons are well positioned to help facilitate this process. The areas where surgeons need to be knowledgeable include: (1) identification of patients for initial breast cancer-related genetic testing, (2) identification of patients who tested negative in the past but now need updated testing, (3) initial cancer genetic testing, (4) retesting of patients who need their genetic testing updated, (5) cancer genetic test interpretation, posttest counseling and management, (6) management of variants of uncertain significance, (7) cascade genetic testing, (8) interpretation of genetic tests other than clinical cancer panels and the counseling and management required, and (9) interpretation of somatic genetic tests and the counseling and management required.

Identifying an early treatment window for predicting breast cancer response to neoadjuvant chemotherapy using immunohistopathology and hemoglobin parameters.

BACKGROUND: Breast cancer pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) varies with tumor subtype. The purpose of this study was to identify an early treatment window for predicting pCR based on tumor subtype, pretreatment total hemoglobin (tHb) level, and early changes in tHb following NAC. METHODS: Twenty-two patients (mean age 56 years, range 34-74 years) were assessed using a near-infrared imager coupled with an Ultrasound system prior to treatment, 7 days after the first treatment, at the end of each of the first three cycles, and before their definitive surgery. Pathologic responses were dichotomized by the Miller-Payne system. Tumor vascularity was assessed from tHb; vascularity changes during NAC were assessed from a percentage tHb normalized to the pretreatment level (%tHb). After training the logistic prediction models using the previous study data, we assessed the early treatment window for predicting pathological response according to their tumor subtype (human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), triple-negative (TN)) based on tHb, and %tHb measured at different cycles and evaluated by the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: In the new study cohort, maximum pretreatment tHb and %tHb changes after cycles 1, 2, and 3 were significantly higher in responder Miller-Payne 4-5 tumors (n = 13) than non-or partial responder Miller-Payne 1-3 tumors (n = 9). However, no significance was found at day 7. The AUC of the predictive power of pretreatment tHb in the cohort was 0.75, which was similar to the performance of the HER2 subtype as a single predictor (AUC of 0.78). A greater predictive power of pretreatment tHb was found within each subtype, with AUCs of 0.88, 0.69, and 0.72, in the HER2, ER, and TN subtypes, respectively. Using pretreatment tHb and cycle 1 %tHb, AUC reached 0.96, 0.91, and 0.90 in HER2, ER, and TN subtypes, respectively, and 0.95 regardless of subtype. Additional cycle 2 %tHb measurements moderately improved prediction for the HER2 subtype but did not improve prediction for the ER and TN subtypes. CONCLUSIONS: By combining tumor subtypes with tHb, we predicted the pCR of breast cancer to NAC before treatment. Prediction accuracy can be significantly improved by incorporating cycle 1 and 2 %tHb for the HER2 subtype and cycle 1 %tHb for the ER and TN subtypes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02092636 . Registered in March 2014.

Small Bowel Follow-Through: Treatment for Small Bowel Obstruction or Delaying the Inevitable?

BACKGROUND: Over 400,000 patients are admitted annually for small bowel obstruction (SBO), of which 20-40% require operative intervention, representing more than 2.3 billion dollars in healthcare expenses. Recurrence of SBO increases with a longer duration of follow-up with up to 15-20% recurrence rates within a five-year period. Small bowel follow-through (SBFT) consisting of serial X-rays with oral contrast has been shown to decrease overall length of stay (LOS) in patients with adhesive SBO. The aim of this study is to determine if SBFT administered to patients with SBO decreases 30-day and up to five-year readmission rates secondary to recurrent SBO. METHODS: The institutional review board (IRB) approved a single institution retrospective study from 2010 to 2020 that included a total of 742 patients. These patients were organized into groups of those who received the SBFT <24 hours after admission (n=40), those who received the SBFT >24 hours (n=198), and the third group of patients who did not receive the SBFT (n=658). Readmission rates <30 days, 70 years along with BMI <25, 25-29.9, 30-34.9, 35-39.9, >40, as well as the number of intraabdominal surgeries, gender, and need for operative intervention during the admission were evaluated to assess for any associations with recurrence. Readmission within 30 days and up to five years were compared. RESULTS: There were no significant differences in recurrence rates between groups with SBFT <24 hours (p=0.338) or SBFT >24 hours (p=0.889) when compared to the no SBFT group. There was nearly a 48% chance of readmission for another episode of an SBO for patients who did not undergo an operative intervention. While patients who underwent operative intervention had around a 29% chance of having a subsequent episode of an SBO. This is consistent with a statistically significant decrease in one-year (p=0.027) recurrences in patients who underwent operative intervention. CONCLUSION: There was no significant difference in recurrences with gender, most BMI groups, or in groups who underwent an SBFT. Operative intervention is associated with a statistically significant decrease in recurrence rates of SBO within one year of presentation.

Evaluation of a National Quality Improvement Collaborative for Improving Cancer Screening.

Importance: Cancer screening deficits during the first year of the COVID-19 pandemic were found to persist into 2021. Cancer-related deaths over the next decade are projected to increase if these deficits are not addressed. Objective: To assess whether participation in a nationwide quality improvement (QI) collaborative, Return-to-Screening, was associated with restoration of cancer screening. Design, Setting, and Participants: Accredited cancer programs electively enrolled in this QI study. Project-specific targets were established on the basis of differences in mean monthly screening test volumes (MTVs) between representative prepandemic (September 2019 and January 2020) and pandemic (September 2020 and January 2021) periods to restore prepandemic volumes and achieve a minimum of 10% increase in MTV. Local QI teams implemented evidence-based screening interventions from June to November 2021 (intervention period), iteratively adjusting interventions according to their MTVs and target. Interrupted time series analyses was used to identify the intervention effect. Data analysis was performed from January to April 2022. Exposures: Collaborative QI support included provision of a Return-to-Screening plan-do-study-act protocol, evidence-based screening interventions, QI education, programmatic coordination, and calculation of screening deficits and targets. Main Outcomes and Measures: The primary outcome was the proportion of QI projects reaching target MTV and counterfactual differences in the aggregate number of screening tests across time periods. Results: Of 859 cancer screening QI projects (452 for breast cancer, 134 for colorectal cancer, 244 for lung cancer, and 29 for cervical cancer) conducted by 786 accredited cancer programs, 676 projects (79%) reached their target MTV. There were no hospital characteristics associated with increased likelihood of reaching target MTV except for disease site (lung vs breast, odds ratio, 2.8; 95% CI, 1.7 to 4.7). During the preintervention period (April to May 2021), there was a decrease in the mean MTV (slope, -13.1 tests per month; 95% CI, -23.1 to -3.2 tests per month). Interventions were associated with a significant immediate (slope, 101.0 tests per month; 95% CI, 49.1 to 153.0 tests per month) and sustained (slope, 36.3 tests per month; 95% CI, 5.3 to 67.3 tests per month) increase in MTVs relative to the preintervention trends. Additional screening tests were performed during the intervention period compared with the prepandemic period (170 748 tests), the pandemic period (210 450 tests), and the preintervention period (722 427 tests). Conclusions and Relevance: In this QI study, participation in a national Return-to-Screening collaborative with a multifaceted QI intervention was associated with improvements in cancer screening. Future collaborative QI endeavors leveraging accreditation infrastructure may help address other gaps in cancer care.

Early-stage invasive breast cancers: potential role of optical tomography with US localization in assisting diagnosis.

PURPOSE: To investigate the potential role of optical tomography in the near-infrared (NIR) spectrum with ultrasonographic (US) localization as a means of differentiating early-stage cancers from benign lesions of the breast. MATERIALS AND METHODS: The protocol was approved by the institutional review boards and was HIPAA compliant; all participants signed an informed consent. One hundred seventy-eight consecutive women (mean age, 52 years; range, 21-89 years) who underwent US-guided biopsy were imaged with a hand-held probe consisting of a coregistered US transducer and an NIR imager. The lesion location provided by coregistered US was used to guide optical imaging. Light absorption was measured at two optical wavelengths. From this measurement, tumor angiogenesis was assessed on the basis of calculated total hemoglobin concentration (tHb) and was correlated with core biopsy results. For patients diagnosed with carcinomas and followed up with subsequent excision, the tHb was correlated with pathologic parameters. RESULTS: There were two in situ carcinomas (Tis), 35 T1 carcinomas, 24 T2-T4 carcinomas, and 114 benign lesions. The mean maximum and mean average tHb of the Tis-T1 group were 102.0 micromol/L +/- 28.5 (standard deviation) and 71.9 micromol/L +/- 18.8, and those of the T2-T4 group were 100.3 micromol/L +/- 26.4 and 67.0 micromol/L +/- 18.3, respectively. The mean maximum and mean average tHb of the benign group were 55.1 micromol/L +/- 22.7 and 39.1 micromol/L +/- 14.9, respectively. Both mean maximum and mean average tHb levels were significantly higher in the malignant groups than they were in the benign group (P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value for Tis-T1 cancers were 92%, 93%, 81%, and 97%. The corresponding values for T2-T4 tumors were 75%, 93%, 69%, and 95%. CONCLUSION: The angiogenesis (tHb) contrast imaged by using the NIR technique with US holds promise as an adjunct to mammography and US for distinguishing early-stage invasive breast cancers from benign lesions.

Genetic issues in patients with breast cancer.

Screening for genetic abnormalities is a relatively complex task requiring detailed training and knowledge. Analysis of a person's genetic makeup has implications not only for that individual but also for their progenitors, offspring, siblings, and spouses. There are potential insurance, employment, and other risks regarding disclosure of this information. With proper training, surgeons or nurses with advanced skills can be qualified to conduct this type of initial analysis. Geneticists may be the ideal professionals to counsel patients. In this article, we explore these and other issues. The goal is to provide the surgeon with the information needed to identify patients at risk for carrying identifiable mutations that might lead to the development of breast cancer.

Optical tomography with ultrasound localization for breast cancer diagnosis and treatment monitoring.

Optical tomography with ultrasound (US) localization uses coregistered ultrasound images to guide optical imaging reconstruction. To simultaneously acquire US images and optical measurements, the authors used a hand-held probe consisting of a commercial US transducer and near-infrared optical imaging sensors of multiple wavelengths. A novel image scheme was used to map the ultrasound-visible lesions for optical imaging reconstruction. As a result, the problem of intense light scattering caused by breast tissue was overcome and reliable tumor hemoglobin concentration and blood oxygen saturation distributions from a group of patients were obtained. These functional parameters are valuable for aiding US diagnosis and for assessing chemotherapy response.

The Learning Preferences of Applicants Who Interview for General Surgery Residency: A Multiinstitutional Study.

BACKGROUND: Learning styles theory posits that learners have distinct preferences for how they assimilate new information. The VARK model categorizes learners based on combinations of 4 learning preferences: visual (V), aural (A), read/write (R), and kinesthetic (K). A previous single institution study demonstrated that the VARK preferences of applicants who interview for general surgery residency are different from that of the general population and that learning preferences were associated with performance on standardized tests. This multiinstitutional study was conducted to determine the distribution of VARK preferences among interviewees for general surgery residency and the effect of those preferences on United States Medical Licensing Examination (USMLE) scores. METHODS: The VARK learning inventory was administered to applicants who interviewed at 3 general surgery programs during the 2014 to 2015 academic year. The distribution of VARK learning preferences among interviewees was compared with that of the general population of VARK respondents. Performance on USMLE Step 1 and Step 2 Clinical Knowledge was analyzed for associations with VARK learning preferences. Chi-square, analysis of variance, and Dunnett's test were used for statistical analysis, with p < 0.05 considered statistically significant. RESULTS: The VARK inventory was completed by a total of 140 residency interviewees. Sixty-four percent of participants were male, and 41% were unimodal, having a preference for a single learning modality. The distribution of VARK preferences of interviewees was different than that of the general population (p = 0.02). By analysis of variance, there were no overall differences in USMLE Step 1 and Step 2 Clinical Knowledge scores by VARK preference (p = 0.06 and 0.21, respectively). However, multiple comparison analysis using Dunnett's test revealed that interviewees with R preferences had significantly higher scores than those with multimodal preferences on USMLE Step 1 (239 vs. 222, p = 0.02). CONCLUSION: Applicants who interview for general surgery residency have a different pattern of VARK preferences than that of the general population. Interviewees with preferences for read/write learning modalities have higher scores on the USMLE Step 1 than those with multimodal preferences. Learning preferences may have impact on residency applicant selection and represents a topic that warrants further investigation.

A safe and simpler diagnosis of gastric schwannomas.

Although gastric schwannomas usually are nonmalignant, these tumors can undergo malignant transformation. For diagnosis, endoluminal routes are believed to decrease the chance of cancerous cell dissemination. We present a case where a percutaneous route was utilized with supporting evidence for the safe use of this method for diagnosis.

Ultrasound-guided optical tomographic imaging of malignant and benign breast lesions: initial clinical results of 19 cases.

The diagnosis of solid benign and malignant tumors presents a unique challenge to all noninvasive imaging modalities. Ultrasound is used in conjunction with mammography to differentiate simple cysts from solid lesions. However, the overlapping appearances of benign and malignant lesions make ultrasound less useful in differentiating solid lesions, resulting in a large number of benign biopsies. Optical tomography using near-infrared diffused light has great potential for imaging functional parameters of 1) tumor hemoglobin concentration, 2) oxygen saturation, and 3) metabolism, as well as other tumor distinguishing characteristics. These parameters can differentiate benign from malignant lesions. However, optical tomography, when used alone, suffers from low spatial resolution and target localization uncertainty due to intensive light scattering. Our aim is to combine diffused light imaging with ultrasound in a novel way for the detection and diagnosis of solid lesions. Initial findings of two early-stage invasive carcinomas, one combined fibroadenoma and fibrocystic change with scattered foci of lobular neoplasia/lobular carcinoma in situ, and 16 benign lesions are reported in this paper. The invasive cancer cases reveal about two-fold greater total hemoglobin concentration (mean 119 micromol) than benign cases (mean 67 micromol), and suggest that the discrimination of benign and malignant breast lesions might be enhanced by this type of achievable optical quantification with ultrasound localization. Furthermore, the small invasive cancers are well localized and have wavelength-dependent appearance in optical absorption maps, whereas the benign lesions appear diffused and relatively wavelength-independent.

The interleukin-1 family of cytokines and receptors in human breast cancer: implications for tumor progression.

We have previously described the expression of interleukin cytokines (IL)-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1ra) in human breast cancer (HBC) tissue. Based on our previous studies, we hypothesize that the IL-1 family of cytokines, antagonists (IL-1ra) and receptors (IL-1RI and IL-1RII) are present within the human breast cancer (HBC) tumor microenvironment and that the IL-1 network of cytokines and receptors within the tumor microenvironment can control tumor cell subpopulation expression of other protumorigenic cytokines such as the angiogenic/growth factor, interleukin-8 (IL-8). To test this hypothesis we characterized the in vivo expression of the IL-1 network in HBC tissues and homogenates by immunohistochemistry (IHC) and ELISA. Additionally, we examined IL-1R expression in HBC cell lines in vitro and in a murine xenograft model by IHC. Finally, we determined the ability of IL-1 to induce IL-8 expression in in vitro using HBC cell lines. We observed that not only are the IL-1 cytokines present in HBC tissue and homogenates, but that IL-1Rs and IL-8 are also present in the HBC tumor microenvironment. Additionally, expression levels for some members of the IL-1/IL-8 network of cytokines correlated with the prognostic indicators, ER/PR. Using HBC cell lines, we observed that HBC cell lines express IL-1Rs in vitro and in the xenograft model. Furthermore, in vitro, HBC cell lines show a spectrum of responsiveness to IL-1 as measured by expression the proangiogenic/mitogenic cytokine IL-8. Our data clearly demonstrate the presence and distribution of IL-1 cytokines and receptors in HBC and suggests that the local expression of IL-1 results in the activation of a population of cells within the HBC tumor microenvironment. This activation of the IL-1/IL-1R cytokine family via autocrine and/or paracrine mechanisms leads to a cascade of secondary protumorigenic cytokines. These secondary signals induce the expression of numerous protumorigenic activities such as the expression of IL-8, and subsequently contribute to angiogenesis, tumor proliferation, and tumor invasion.

In vitro demonstration of breast cancer tumor cell sub-populations based on interleukin-1/tumor necrosis factor induction of interleukin-8 expression.

Interleukin-8 (IL-8) has been identified as an angiogenesis factor (AF) as well as a tumor cell chemotactic factor and mitogen. Recent in vivo studies have demonstrated the expression of IL-8, IL-1 and TNF, as well their receptors, on various sub-populations of tumor cells in human breast cancer (HBC). Since pro-inflammatory cytokines such as IL-1 and TNF are known inducers of IL-8 in non-tumor cells, we hypothesize that IL-1/TNF may act as an IL-8 inducer in HBC, and thus enhance HBC tumor progression. To begin to test this hypothesis, we evaluated the ability of: a) human breast cancer cell lines (BCC) and normal human breast epithelial cell lines (BEC) to produce IL-8 in vitro; and b) IL-1 and TNF to regulate the expression of IL-8. In general, basal IL-8 expression was low in all 8 cell lines examined. TNF-alpha and TNF-beta induced a 3- to 24-fold increase in IL-8 protein expression of BEC, and a 2- to 8-fold increased IL-8 expression in estrogen-independent BCC cell lines and no significant IL-8 expression in estrogen-dependent cell lines. Conversely, IL-1alpha and IL-1beta, induced a 5- to 104-fold stimulation of BEC and a 330 to 1,138-fold increase in IL-8 expression in estrogen independent BCC. These observations demonstrate the ability of HBC cells to produce IL-8 in vitro and further indicate that IL-1 is a potent inducer of IL-8 expression by BEC and BCC. Furthermore, this in vitro data support the hypothesis, that within the HBC tumor microenvironment, tumor cells exist that respond to pro-inflammatory cytokine (IL-1) stimulation (i.e. MDA-MB-231) and those that do not (i.e. MCF-7). Additionally, HBC tumor cell lines that can be induced to express high levels of IL-8 tend to be associated with a more aggressive phenotype.