Localized Breast Research Articles

Abstract PS19-02: Gut pathogen, Bacteroides fragilis promotes breast cancer liver and lung metastasis

Abstract Background: The last decade established significant contributions of microbiome to many organ specific cancers. Existence of distinct breast microbiota has been recently established but their biological impact in breast cancer progression remains elusive. A few recent studies suggested the existence of distinct breast microbiota and a shift in microbial community composition in diseased breast compared to normal breast however, their functional impact and underlying mechanisms are unknown. Present study was designed to examine the contribution of pro-carcinogenic bacteria in breast cancer initiation, progression and metastasis. Utilizing extensive data mining and metagenomic analyses, we discovered the presence of toxin producing enterotoxigenic Bacteroides fragilis (ETBF) in malignant breast. ETBF is a pro-carcinogenic bacteria known for its potential to initiate and/or promote colon cancer and its pathogenicity has been attributed to its unique toxin B. fragilis toxin (BFT)’. Results: Using mammary intraductal model we discovered that ETBF can successfully colonize the breast confirmed by qPCR and Fluorescent in situ hybridization where it induces local inflammation, fibrosis and hyperproliferation of breast epithelial cells. Mice bearing gut ETBF infection exhibit significant circulating BFT confirmed by qPCR and ELISA and distinct morphological alterations in mammary gland as observed from whole breast mounting and histological evaluation. Gut colonization with ETBF rapidly induces hyperplasia in mammary glands with systemic and local breast inflammation validated by flow cytometry, immunohistochemistry and cytokine profiling. While no changes are observed in cell growth and clonogenicity upon BFT treatment, significant increase in migration and invasion potential and decreased adhesion of MCF10A and MCF7 cells are observed. BFT leads to prominent cytoskeletal reorganization, and increase in migration, invasion and stemness potential of breast cancer cells. Our results indicate that breast cancer cells exposed to BFT ensue to exhibit increase tumor growth, form multifocal tumors and show a striking increase in tumor-initiating cells upon in vivo limiting dilution in immunocompromised mice exhibiting retention of ‘BFT memory’ from the initial exposure. Mechanistically, RNA-sequencing shows enrichment of βcatenin and Notch pathway in secondary tumors derived from BFT-exposed breast cancer cells. Inhibitors of βcatenin and Notch axis abrogates BFT-induced migration and invasion potential indicating the functional importance of this axis. Intriguingly, gut colonization with ETBF at a physiologically relevant level strongly induces growth and metastatic progression of 4T1 tumor cells implanted in mammary ducts monitored by whole animal bioluminescent imaging. In vivo and ex vivo analyses of tumors and distant organs reveal a significant induction of lung and liver metastasis of breast cancer by ETBF while gut colonization with non-toxigenic Bacteroides fragilis (NTBF) does not exhibit any tumor-augmenting impact. We mechanistically evaluate the oncogenic impact of alpha bug ETBF on breast cancer progression and its role in promoting liver and lung metastasis using multiple mice models and multiple techniques including multi-color flow cytometry, immunohistochemistry, quantitative PCR, multiplexed ELISA, ex vivo functional assays and western blotting. Conclusion: Collectively, these findings present the first evidence to show that gut colonization with Bacteroides fragilis rapidly induces inflammation, fibrosis and hyperplasia in the breast. In syngeneic breast cancer model, gut colonization with ETBF aggravates breast cancer progression and induces enhanced lung and liver metastasis via systemic immune modulation, cytokine synthesis and activation of pro-oncogenic pathways. Citation Format: Sheetal Parida, Sumit Siddharth, Guannan Wang, Himavanth Gatla, Shaoguang Wu, Brian Ladle, Kathleen Gabrielson, Cynthia L Sears, Dipali Sharma. Gut pathogen, Bacteroides fragilis promotes breast cancer liver and lung metastasis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-02.

Abstract PS1-34: Oncological safety and patient journey with magseed™ localised breast conserving surgery

Abstract Introduction: Wire localised wide local excision (W-WLE) has been the standard of care for impalpable breast lesions and requires insertion of the wire on the same day as the surgery. Logistics of same day localisation can lead to a chaotic morning for the patients with long uncomfortable waiting times prior to their surgery. Transporting patients across the hospital and at times between different sites can add to poor patient experience and inefficient theatre utilisation. Magseed localised wide local excision (M-WLE) is an alternative to W-WLE. Magseed is a 5mm non-radioactive paramagnetic seed inserted radiologically and in the UK it is licensed for insertion up to 30 days in advance. M-WLE was started for routine use in our Unit in July 2019. We compare the safety parameters and length of hospital stay (LOS) in patients undergoing M-WLE to W-WLE. Methods: All M-WLEs performed at a single institution over an 8 month period (Jul 19 - Feb 20) were included. These were compared to a historic matched cohort of W-WLEs performed over 8 months (Jan 18 - Aug 18) which would have been suitable for Magseed localisation. The suitability for Magseed localisation was decided by a breast radiologist based on local objective criteria. Intra-operative cavity shaves were performed based on specimen X-ray and re-excisions were performed where there was tumour at or < 1 mm from inked margin. Exclusion criteria for Magseed localisations included - i. multiple lesions requiring 2 or more wires and ii. Depth of lesion from skin (>3cm on ultrasound or >7cm deep in central breast on mammogram). Data including patient demographics, type of localisation, successful placements, pathology, re-excision rates, tumour size, and length of stay (LOS) was collected and analysed. Results: Over the 16 months, 319 patients underwent localised WLEs. 238 patients were included in the study and 81 excluded. Patient demographics and tumour characteristics are detailed in Table 1. There is no significant difference in the intra-operative cavity shaves between the two groups. A significant difference in the re-excisions rates favouring the M-WLE group despite no significant difference in the mean tumour to specimen ratio was seen. (Table 2) The median waiting time to surgery from the time of admission was observed to be significantly shorter in the M-WLE group (4h15mins vs 7h03mins, p<0.01). There was no significant difference in the median LOS between the two groups (M-WLE 13h44mins, W-WLE 13h56mins, p=0.36). The overall day surgery rates were comparable in the two groups (M-WLE 75.2%, W-WLE 75.1%, p=0.99). Conclusion: In the present series, M-WLE has been shown to be oncologically safe and non-inferior to W-WLE with a significantly lower re-excision rate. In addition to this, the reduced pre-operative waiting time on the day of surgery in the M-WLE group will have a positive effect on the patient journey. Further research should focus on the potential impact on day-bed utilisation and theatre efficiency. Table 1: Patient demographics and tumour characteristicsMagseed™Wirep valuen105133Median age (years)64 (34-87)60 (28-82)0.05Median BMI28.2 (17-54.4)28.3 (18.8-43.1)0.62PathologyInvasive+/-DCIS851100.31DCIS1715Others38Mean tumour diameter (mm)Invasive+/-DCIS15.19 (3-55)15.52 (1-15)0.82DCIS9.41 (3-45)17.12 (3-55)0.13 Table 2: Tumour to specimen ratio, further intra-operative cavity shaves and re-excision ratesMagseed™Wirep valuen102125Mean Tumour/Specimen RatioInvasive+/-DCIS8.8%18.1%0.20DCIS18.4%24.8%0.75Further intra-operative cavity shavesTotal48 (47.0%)68 (54.4%)0.27Invasive+/-DCIS28/64 (43.7%)56/102 (54.9%)0.16DCIS7/15 (46.6%)8/15 (53.3%)0.71Oncoplastic procedures: Invasive+/-DCIS12/21 (57.1%)4/7 (57.1%)1Oncoplastic procedures: DCIS1/2 (50%)0/1 (0%)NARe-excisions of marginsTotal3 (2.9%)13 (10.4%)0.03Invasive+/-DCIS3/64 (4.6%)8/102 (7.8%)0.4DCIS0/15 (0%)5/15 (33.3%)NAOncoplastic procedures: Invasive+/-DCIS0/21 (0%)0/7 (0%)NAOncoplastic procedures: DCIS0/2 (0%)0/1 (0%)NA Citation Format: Kirti Katherine Kabeer, Manoj S Gowda, Zatinahhayu MohdIsa, Megan Thomas, Vallipuram Gopalan, Sadaf Jafferbhoy, Soni Soumian, Sankaran Narayanan, Robert Kirby, Sekhar Marla. Oncological safety and patient journey with magseed™ localised breast conserving surgery [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-34.

Abstract PD11-05: Diabetes decreases overall survival in women with breast cancer in the southern community cohort study

Abstract Background:Factors contributing to breast cancer survival disparities in underrepresented racial and ethnic groups and low-income populations are poorly understood as few clinical trials and population based studies have included these underserved populations. The Southern Community Cohort Study (SCCS), a prospective cohort of underserved, low-income adults with high representation of Black participants, provides a unique opportunity to evaluate such disparities in cancer outcomes. A previous study utilizing SCCS data found no evidence of increased breast cancer risk among women with diabetes in this population. The purpose of this study was to evaluate the association of diabetes with overall survival in women with breast cancer in the SCCS. Methods:The SCCS enrolled approximately 86,000 participants aged 40-79 from 12 southeastern states between 2002-2009, 86% of whom were enrolled at Community Health Centers. This analysis includes women diagnosed with incident localized breast cancers identified through annual cohort linkage with 12 state cancer registries. Demographic data including participant age at breast cancer diagnosis, self-reported history of diabetes (patient answered yes to “has a doctor ever told you that you have diabetes”), body mass index (BMI), race, household income, and insurance coverage were obtained from baseline surveys, cancer type and stage data from state cancer registries, and survival data from death registries. Survival time was defined as the number of months between initial breast cancer diagnosis and death from any cause. Descriptive characteristics including mean (standard deviation) or number (%) were used to summarize demographics. We used Pearson Chi-squared analysis to examine the association between diabetes and overall survival. Multivariable Cox proportional hazards regression was used to evaluate overall survival and diabetes, adjusting for covariates including age (continuous), race, BMI (categorical by WHO classifications), household income (binary – annual income <$25,000, annual income >=$25,000), insurance coverage, cancer subtype, and cancer stage). Results:We identified a total of 1,347 women diagnosed with breast cancer. Of these, 1,016 were diagnosed with localized disease (stage 1-3) and comprised our analytic sample. Difference in denominators reflects missing data. The women were predominantly Black (667/1,016, 65.6%), low income (719/1,016 annual income less than $25,000, 70.8%), and insured (Private insurance 220/763, 28.8%; Medicare 331/763, 43.4%; Medicaid 178/763, 23.3%). Average age at diagnosis was 60.7 years (SD 9.1, IQR 41-88). Approximately one quarter of the patients (258/994, 26.0%) self-reported diabetes and 59.6% (605/1,016) were obese (BMI >=30). The breast cancer immunohistochemistry subtypes in this cohort of women included HR+HER2- (392/564, 69.5%), HR+,HER2+ (55/564, 9.8%), HR-,HER2+ (31/564, 5.5%), and HR-HER2- (86/564, 15.3%). Women with diabetes had lower overall survival (174/258, 67.4%) than women without diabetes (587/746, 79.8%) (p<0.0001). In the adjusted multivariate Cox regression model, diabetes significantly decreased overall survival in women with breast cancer, hazard ratio 1.87, 95% Confidence Interval [CI] = 1.12-3.09. Conclusion: In a low-income, predominantly Black population with incident localized breast cancer, decreased overall survival was observed among women diabetes compared to those without diabetes. Future studies should explore additional biological, societal, and socio-economic factors affecting survival among women with breast cancer in medically underserved minority populations. Citation Format: Lucy B. Spalluto, Sonya Reid, Diane Haddad, Tuya Pal, Ingrid A. Mayer, Xiao-ou Shu, Maureen Sanderson, Wei Zheng, William J. Blot, Loren Lipworth. Diabetes decreases overall survival in women with breast cancer in the southern community cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD11-05.

Abstract PS7-34: The association of race and socioeconomic status with overall survival in women with breast cancer in the southern community cohort study

Abstract Background:Breast cancer outcomes in minority and low socioeconomic status populations are not clearly defined due to underrepresentation of these underserved populations in breast cancer clinical trials and population-based studies. The Southern Community Cohort Study (SCCS), a prospective cohort of underserved, predominantly Black participants, provides a unique opportunity to evaluate disparities in breast cancer outcomes. We sought to examine the association between race and socioeconomic status (SES) and overall survival (OS) in women with localized breast cancer in the SCCS. Methods:The SCCS enrolled approximately 86,000 participants aged 40-79 from 12 Southeastern states between 2002-2009, 86% of whom were enrolled at Community Health Centers. This analysis includes women diagnosed with incident localized breast cancer (stage I-III) identified through annual cohort linkage with 12 state cancer registries through December 20, 2017. Demographic data including participant age, self-reported history of diagnosed diabetes, body mass index (BMI), race, annual household income, and insurance coverage were obtained from baseline surveys. Tumor grade and stage were obtained from state cancer registries, and survival data were obtained from death registry records. Immunohistochemical (IHC) subtype was determined from tumor estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status obtained from cancer registry records and pathology reports. Survival time was defined as the number of months between initial breast cancer diagnosis and death from any cause. Descriptive analyses including mean (standard deviation) and number (%) were used to summarize clinical and sociodemographic characteristics by race. Multivariable Cox survival analysis was used to evaluate OS by race and annual household income, adjusting for age, insurance, stage, IHC subtype, diabetes, and BMI. Results:Of the 1347 women diagnosed with incident breast cancer, 1016 had localized disease (stage I-III) and comprised our analytic sample. Compared to White women, Black women were more likely to have lower income, higher prevalence of triple negative breast cancer (TNBC), grade III tumors and stage III breast cancer (Table 1). After adjusting for clinical and sociodemographic factors, Black women had similar OS compared to White women (HR 0.67; 95% CI 0.42-1.07). However, after adjusting for race, women with a household income ≥ $25,000 had an improved OS compared to those with annual household income < $25,000 (HR 0.53; 95% CI 0.30-0.93). Conclusion: In a low-income, medically underserved population, Black women with localized breast cancer had similar OS compared to White women. However, socioeconomic disparities were observed, with worse OS for women with low annual household income. Future studies focused on minority, underserved groups are imperative to better understand the non-biological and biological factors contributing to disparities in survival among women with breast cancer. Table 1. Patient characteristics overall and by racePatient CharacteristicsTotal(N=1016)Black(N=667)White(N=349)P-value*Age at diagnosis, years (Mean, SD)61 (9)60 (9)63 (9)Income, annual household (N, %) < $25,000 ≥ $25,000719 (71)297 (29)503 (75)164 (25)216(62)133 (38)<0.001Insurance (N, %) Private insurance Medicare Medicaid Uninsured220 (29)331 (43)178 (23)34 (5)152 (29)209 (40)139 (26)26 (5)68 (29)122 (51)39 (16)8 (3)0.005Diabetes (N, %) No history of diabetes History of diabetes736 (74)258 (26)469 (72)183 (28)267 (78)75 (22)0.04BMI, kg/m2 (N, %) 18.5-30.0 kg/m2 30.0+ kg/\\411 (40)605 (60)239 (36)428 (64)172 (49)177 (51)<0.001IHC subtype (N, %) HR+,HER2- HR+,HER2+ HR-,HER2- TNBC392 (69)55 (10)34 (6)86 (15)255 (65)38 (10)26 (7)75 (19)137 (79)17 (10)8 (5)11 (6)0.001Grade (N, %) I II III188 (20)383 (41)372 (39)111 (18)239 (38)277 (44)77 (24)144 (46)95 (30)<0.001Stage (N, %) I II III460 (45)383 (38)173 (17)278 (42)261 (39)128 (19)182 (52)122 (35)45 (13)0.003HR = Estrogen receptor (ER) and/or progesterone receptor (PR)* denotes p-value for White compared Black women Citation Format: Sonya Reid, Lucy B Spalluto, Diane Haddad, Tuya Pal, Ingrid Mayer, Xiao-ou Shu, Wei Zheng, Maureen Sanderson, William Blot, Loren Lipworth. The association of race and socioeconomic status with overall survival in women with breast cancer in the southern community cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-34.

The relationship between NFKB, HER2, ER expression and anthracycline -based neoadjuvan chemotherapy response in local advanced stadium breast cancer: A cohort study in Eastern Indonesia

IntroductionNeoadjuvant chemotherapy has become the standard form of treatment for locally advanced breast cancer. Chemoresistence is a problem that limits the effectiveness of chemotherapy. Therefore, predictive biomarkers are needed to choose the appropriate chemotherapy to the right patient. The role of NF-кb expression as a predictive biomarker of neoadjuvant chemotherapy response needs to be investigated in patients with locally advanced breast cancer who are treated with a regimen of cyclophosphamide-doxorubicin-5FU (CAF). MethodsThis observational study used the prospective cohort method to examine 62 samples. CAF was administered at 3-week intervals for 3 cycles of chemotherapy. The data utilized in this study include the positive and negative expression of NF-κB, ER, and HER2 overexpression. The cases were divided into groups that were responsive and non-responsive to the neoadjuvant chemotherapy. ResultsThe average age in the youngest group was 26 years, and that in the oldest was 66 years. The highest age group was subjects in their 50s, which had 26 cases (41.9%). The majority of the cases were moderate grade with 38 cases (61.3%). The percentage of responsive subjects was higher in the groups with negative NF-κB expression (82.5%), positive HER2 status (85.7%), and negative ER status (71.9%). It was found that 37 cases (59.7%) were responsive to CAF, while 25 cases (40.3%) were non-responsive. There was a significant relationship between NF-κB expression and chemotherapy response (p < 0.05), and the percentage of responsive subjects was higher among those with negative NF-κB expression (82.5%) than positive NF-κB expression (18.2%). ConclusionNF-κB expression, ER status, and HER2 have a significant relationship with the response to anthracycline-based neoadjuvant chemotherapy for local advanced breast cancer, and NF-κB expression has the most significant relationship with the chemotherapy response. Therefore, NF-κB expression should be considered as a predictive biomarker for the response to CAF regimens.

Ancestry-associated transcriptomic profiles of breast cancer in patients of African, Arab, and European ancestry

Breast cancer largely dominates the global cancer burden statistics; however, there are striking disparities in mortality rates across countries. While socioeconomic factors contribute to population-based differences in mortality, they do not fully explain disparity among women of African ancestry (AA) and Arab ancestry (ArA) compared to women of European ancestry (EA). In this study, we sought to identify molecular differences that could provide insight into the biology of ancestry-associated disparities in clinical outcomes. We applied a unique approach that combines the use of curated survival data from The Cancer Genome Atlas (TCGA) Pan-Cancer clinical data resource, improved single-nucleotide polymorphism-based inferred ancestry assignment, and a novel breast cancer subtype classification to interrogate the TCGA and a local Arab breast cancer dataset. We observed an enrichment of BasalMyo tumors in AA patients (38 vs 16.5% in EA, p = 1.30E − 10), associated with a significant worse overall (hazard ratio (HR) = 2.39, p = 0.02) and disease-specific survival (HR = 2.57, p = 0.03). Gene set enrichment analysis of BasalMyo AA and EA samples revealed differences in the abundance of T-regulatory and T-helper type 2 cells, and enrichment of cancer-related pathways with prognostic implications (AA: PI3K-Akt-mTOR and ErbB signaling; EA: EGF, estrogen-dependent and DNA repair signaling). Strikingly, AMPK signaling was associated with opposing prognostic connotation (AA: 10-year HR = 2.79, EA: 10-year HR = 0.34). Analysis of ArA patients suggests enrichment of BasalMyo tumors with a trend for differential enrichment of T-regulatory cells and AMPK signaling. Together, our findings suggest that the disparity in the clinical outcome of AA breast cancer patients is likely related to differences in cancer-related and microenvironmental features.

Comparison of survival in non-metastatic inflammatory and other T4 breast cancers: a SEER population-based analysis

BackgroundPrevious studies have reported poor survival rates in inflammatory breast cancer (IBC) patients than non-inflammatory local advanced breast cancer (non-IBC) patients. However, until now, the survival rate of IBC and other T4 non-IBC (T4-non-IBC) patients remains unexplored.MethodsSurveillance, Epidemiology, and End Results (SEER) database was searched to identify cases with confirmed non-metastatic IBC and T4-non-IBC who had received surgery, chemotherapy, and radiotherapy between 2010 and 2015. IBC was defined as per the American Joint Committee on Cancer (AJCC) 7th edition. Breast Cancer-Specific Survival (BCSS) was estimated by plotting the Kaplan-Meier curve and compared across groups by using the log-rank test. Cox model was constructed to determine the association between IBC and BCSS after adjusting for age, race, stage of disease, tumor grade and surgery type.ResultsOut of a total of 1986 patients, 37.1% had IBC and mean age was 56.6 ± 12.4. After a median follow-up time of 28 months, 3-year BCSS rate for IBC and T4-non-IBC patients was 81.4 and 81.9%, respectively (log-rank p = 0.398). The 3-year BCSS rate in HR−/HER2+ cohort was higher for IBC patients than T4-non-IBC patients (89.5% vs. 80.8%; log-rank p = 0.028), and in HR−/HER2- cohort it was significantly lower for IBC patients than T4-non-IBC patients (57.4% vs. 67.5%; log-rank p = 0.010). However, it was identical between IBC and T4-non-IBC patients in both HR+/HER2- (85.0% vs. 85.3%; log-rank p = 0.567) and HR+/HER2+ (93.6% vs. 91.0%, log-rank p = 0.510) cohorts. After adjusting for potential confounding variables, we observed that IBC is a significant independent predictor for survival of HR−/HER2+ cohort (hazards ratio [HR] = 0.442; 95% CI: 0.216–0.902; P = 0.025) and HR−/HER2- cohort (HR = 1.738; 95% CI: 1.192–2.534; P = 0.004).ConclusionsPatients with IBC and T4-non-IBC had a similar BCSS in the era of modern systemic treatment. In IBC patients, the HR−/HER2+ subtype is associated with a better outcome, and HR−/HER2- subtype is associated with poorer outcomes as compared to the T4-non-IBC patients.

Study protocol: a pilot quasi-experimental trial of tele-rehabilitation and tele-drain care post-mastectomy

BackgroundBreast cancer is the leading cancer affecting women in Singapore. Its survivors commonly experience decline in physical function and quality of life post-mastectomy, due to their upper limb morbidity and wound issues. Rehabilitation can address the aforementioned issues. When rehabilitation is accessible and easy to adhere, it can optimize recovery.Home-based tele-rehabilitation guided by healthcare professionals and self-managed by patients can potentially optimize the patients’ adherence to rehabilitation and recovery. With that in mind, a team of breast cancer specialists (oncologists, nurses, and therapists) in Singapore has developed one of the first tele-rehabilitation systems for local women undergoing a unilateral mastectomy. To our knowledge, no such systems have been evaluated or proven effective as a treatment option among local breast cancer patients with acute disabilities.MethodsThis is a pilot quasi-experimental trial that aims to evaluate the feasibility of tele-rehabilitation and tele-drain care compared to usual care. Up to 40 patients (20 per group) will be recruited for this trial. They will be assigned to an intervention group that receives rehabilitation via a tele-rehabilitation system or a control group that receives rehabilitation in person at their clinic. The primary outcome of this trial is rehabilitation participation (i.e., the time spent on rehabilitation). The secondary outcomes are upper extremity functioning, perceived health, and quality of life.DiscussionAs part of this pilot trial, patients who opt in for the tele-rehabilitation will be asked to share their experience with and thoughts on the tele-rehabilitation system. With the evidence obtained from the tele-rehabilitation patients of this trial, we will be able to improve the current system for our future trial. Further, our additional data on rehabilitation participation, physical function, and quality of life will help us design a sufficiently powered future main trial.Trial registrationThe trial was approved by the National Healthcare Group’s Domain Specific Review Board (#2019/00283) and registered with www.ClinicalTrials.gov (#NCT04269967) in February 2020.

Development of near-infrared imaging agents for detection of junction adhesion molecule-A protein

IntroductionProstate and breast cancer are the most prevalent primary malignant human tumors globally. Prostatectomy and breast conservative surgery remain the most common definitive treatment option for the >500,000 men and women newly diagnosed with localized prostate and breast cancer each year only in the US. Morphological examination is the mainstay of diagnosis but margin under-sampling of the excised cancer tissue may lead to local recurrence. In despite of the progress of non-invasive optical imaging, there is still a clinical need for targeted optical imaging probes that could rapidly and globally visualize cancerous tissues. MethodsElevated expression of junctional adhesion molecule-A (JAM-A) on tumor cells and its multiple pro-tumorigenic activity make the JAM-A a candidate for molecular imaging. Near-infrared imaging probe, which employed anti-JAM-A monoclonal antibody (mAb) phthalocyanine dye IR700 conjugates (JAM-A mAb/IR700), was synthesized and used to identify and visualize heterotopic human prostate and breast tumor mouse xenografts in vivo. ResultsThe intravenously injected JAM-A mAb/IR700 conjugates enabled the non-invasive detection of prostate and breast cancerous tissue by fluorescence imaging. A single dose of JAM-A mAb/IR700 reduced number of mitotic cancer cells in vivo, indicating theranostic ability of this imaging agent. The JAM-A mAb/IR700 conjugates allowed us to image a specific receptor expression in prostate and breast tumors without post-image processing. ConclusionThis agent demonstrates promise as a method to image the extent of prostate and breast cancer in vivo and could assist with real-time visualization of extracapsular extension of cancerous tissue.

The Immutable Burden of Racial Disparities in Breast Cancer

The Immutable Burden of Racial Disparities in Breast Cancer

Favourable outcome of patients with breast cancer brain metastases treated with dual HER2 blockade of trastuzumab and pertuzumab.

Background:Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown.Methods:Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into ‘TP’, ‘other-HER2-targeted therapy’ and ‘no-HER2-targeted therapy’ according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM).Results:A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 versus 17 versus 3 months, p < 0.001; log-rank test). Among radiologically re-assessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission (CR), 8/14 patients (57.1%) partial intracranial remission (PR), 1/14 patients (7.1%) stable intracranial disease (SD) and 0/14 patients (0.0%) progressive intracranial disease (PD) as best response resulting in an intracranial objective response rate (iORR) of 92.9% and an intracranial clinical benefit rate (iCBR) of 100.0%.Conclusion:First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.

Granular cell tumor presenting as subcutaneous nodule mimicking local recurrent breast cancer: A diagnosis by fine needle aspiration cytology

Granular cell tumor presenting as subcutaneous nodule mimicking local recurrent breast cancer: A diagnosis by fine needle aspiration cytology

A mitochondrion-targeted BODIPY-Ir(III) conjugate as a photoinduced ROS generator for the oxidative destruction of triple-negative breast cancer cells.

Photodynamic therapy (PDT) provides an alternative option to root out localized triple-negative breast cancer (TNBC) and has been experiencing a surge of research interest over recent years. In this study, we put forward a paradigm of designing novel transition metal-based PSs with the following characteristics: favorable cell-permeability, significant light-harvesting ability and prominent ROS yield. A novel BODIPY-Ir(III) conjugate has been designed as a photoinduced ROS (1O2, ˙OH and ˙O2-) generator. BODIPY-Ir is highly photoactive in subduing cancer cells in the PDT regimen with PI values ranging from 172 to 519 and EC50 in the nanomolar regime. Among various cancerous cell lines, TNBC was especially sensitive to BODIPY-Ir-mediated PDT, with a stunning EC50 value of 4.32 nM (PI = 519) under a moderate flux of visible-light irradiation (500 nm, 10.5 mW cm-2). BODIPY-Ir mainly accumulates in mitochondria and induces cell apoptosis under irradiation. Furthermore, the nanomolar antiproliferative activity of BODIPY-Ir is retained under hypoxia (2.5% O2). This work sheds light on instilling the O2-independent type I mechanism and conferring a red-shift absorption to metal-based PSs which fundamentally facilitate the clinical translation of PSs.

Breast Self-examination Practice and Associated Factors Among Women of Reproductive Age in Adama Town, Oromia Regional State, Ethiopia

Breast Self-Examination is the process where by a woman examines her own breasts by seeing and feeling with fingers to detect breast lump or swelling. More than 90% cases of breast cancer are detected by women themselves. Poor practice of breast self-examination is usually associated with patient delay. The five-year survival rate for a localized breast cancer is 84%. Community based breast self-examination practice is low in the country specifically in the present study area. Thus this study aimed to assess breast self-examination practice and associated factors among women of reproductive age in Adama Town, Oromia Regional State, Ethiopia in 2017EC. This Community based- cross sectional quantitative study was conducted using a random sample and multistage sampling procedure by administering pretested structured questionnaire to the population of 765 reproductive age women. The collected data were cleaned, coded and entered into Epi-Info version 7 and exported to SPSS version 20 for analysis. Descriptive statistics, bivariate and multivariable logistic regression were computed. Adjusted odds ratio (AOR) with 95% confidence interval (CI) was used to assess the association among study variables. This study indicated that the overall prevalence of breast self- examination practice was 51.4% with 95% CI (48.1, 55.2). Factors associated with breast self-examination practice were above secondary education (AOR, 6.38; 95% CI: 2.87, 14.16), secondary education (AOR, 5.03; 95% CI: 2.24, 11.30), knowing someone suffering from breast cancer (AOR, 1.98, 95% CI: 1.27, 3.09), and fear of breast cancer from family history (AOR, 12.38, 95% CI: 6.36, 24.10) were having statically significant and positive association with breast self-examination practice. This study revealed that breast self-examination practice was high. Oromia Regional Health Bureau, Adama Town Health Office, women’s and children’s affair offices and other stake holders should disseminate teaching materials that address the benefit of breast self-examination practice. Health professionals should teach the community about the advantage of breast self-examination practice through mass media, awareness raising campaigns, and celebration of breast cancer day.

Pre-treatment high body mass index is associated with poor survival in Asian premenopausal women with localized breast cancer.

Background: Obesity is associated with poor prognosis in breast cancer patients. This study aimed to evaluate the effect of obesity measured by body mass index (BMI) on survival of Taiwanese breast cancer patients in a single institution.Methods: We observed 5000 patients who were diagnosed with stage I-III breast cancer between 1990 and 2005. Information on BMI at diagnosis, and clinical follow-up for disease recurrence and death, up to 20 years post-diagnosis were available. BMI (in kg/m2) categories included normal weight (BMI<24), overweight (24≤BMI<27), and obesity (BMI≥27), according to recommendations from the Bureau of Health Promotion of Taiwan. The role of BMI and other known prognostic factors for patient survival were evaluated in this patient cohort.Results: Obesity was associated with advanced stage, higher nuclear grade, and higher percentages of estrogen receptor (ER) positive. The median age of patients with a higher BMI was greater than the median age of patients with a lower BMI. Obesity was an independent prognostic factor of overall survival (OS) (P<0.001), but not disease-free survival (DFS) (P=0.067). We subsequently analyzed the impact of age-stratified BMI (age<50 and age≥50 years) to ameliorate the impact of age bias. Following subset analyses, obesity correlated with shorter DFS (P=0.004) and OS (P=0.009) only in women<50 years of age. Multivariate analysis revealed that BMI was an independent prognostic factor for both DFS and OS in this group of patients. Subset analysis revealed that in women <50 years old, the impact of BMI on survival was associated with higher stage, ER negativity.Conclusion: BMI is an independent prognostic factor of OS and DFS in breast cancer patients aged<50 years. Although the cause-effect relationship between obesity and survival is unclear, we recommend that weight control measures in young breast cancer survivors should be considered.

Effects of an Exercise and Nutritional Intervention on Circulating Biomarkers and Metabolomic Profiling During Adjuvant Treatment for Localized Breast Cancer: Results From the PASAPAS Feasibility Randomized Controlled Trial.

Purpose:Exercise has been shown to improve physical and psychological conditions during cancer therapy, but mechanisms remain poorly understood. The purpose of the present study was to report the results of cancer-related biomarkers and metabolomics outcomes from the PASAPAS feasibility study.Methods:In the PASAPAS randomized controlled trial, 61 women beginning adjuvant chemotherapy for localized breast cancer were randomized in a 6-month program of weekly aerobic exercises associated with nutritional counseling versus usual care with nutritional counseling. In the present analysis of 58 women for whom blood samples were available, first, circulating levels of biomarkers (ie, insulin, insulin-like growth factor 1, estradiol, adiponectin, leptin, interleukin-6, and tumor necrosis factor α) were measured at baseline and 6-month follow-up. Changes in biomarkers were compared between exercisers (n = 40) and controls (n = 18) using mixed-effect models. Second, serum metabolites were studied using an untargeted 1H nuclear magnetic resonance spectroscopy, and orthogonal partial least squares analyses were performed to discriminate exercisers and controls at baseline and at 6 months.Results:Over the 6-month intervention, no statistically significant differences were observed between exercisers and controls regarding changes in biomarkers and metabolomic profiles.Conclusion:The present analysis of the PASAPAS feasibility trial did not reveal any improvement in circulating biomarkers nor identified metabolic signatures in exercisers versus controls during adjuvant breast cancer treatment. Larger studies preferably in women with poor physical activity level to avoid ceiling effect, testing different doses and types of exercise on additional biological pathways, could allow to clarify the mechanisms mediating beneficial effects of physical exercise during cancer treatment.Trial registration:ClinicalTrials.gov Identifier: NCT01331772. Registered 8 April 2011, https://clinicaltrials.gov/ct2/show/NCT01331772?term=pasapas&rank=1

Breast cancer recurrence risk after hormonal contraceptive use in survivors of reproductive age

ObjectiveTo assess the risk of recurrence with hormonal contraceptive use in breast cancer survivors of reproductive age. Study designIn this retrospective study, women ages 18–51 years who were diagnosed with primary stage 0–3 breast cancer between 2006–2016 and subsequently entered remission were included. Patients with missing information within the cancer registry or electronic medical record and those with a history of hysterectomy and/or sterilization procedure prior to diagnosis were excluded. Hormonal contraception use was defined as being prescribed an oral contraceptive pill (OCP), patch, vaginal ring, medroxyprogesterone injection, etonogestrel implant, or levonorgestrel-releasing intrauterine device (IUD). Women were separated into two groups, hormonal contraceptive users and non-users. Basic descriptive and inferential statistics were used to compare groups as appropriate. The primary outcome reviewed was local or distant breast cancer recurrence. Secondary outcomes included all-cause mortality and pregnancy. ResultsFollowing exclusions, 1370 women remained in the cohort. Ninety-seven women (7.08 %) received a prescription for a form of hormonal contraception. When comparing groups, hormonal contraceptive users were more likely to be between 18−40 years of age (46.39 % vs. 17.99 % non-users;P < 0.01) and never smokers (68.04 % vs. 38.57 % non-users; P < 0.01). Patients did not differ between groups based on any other demographic or cancer-related characteristic, including tumor hormone receptor expression. Overall, 92 patients (6.72 %) experienced local or distant recurrence during the study period. Recurrence did not differ between groups (6.19 % users vs. 6.76 % non-users; P = 0.83). All-cause mortality and pregnancy rates also did not differ between hormonal contraceptive users and non-users. ConclusionThe study shows no increased risk of recurrence associated with hormonal contraceptive use after breast cancer diagnosis and remission.

Exploring Herbal Medicine Use during Palliative Cancer Care: The Integrative Physician as a Facilitator of Pharmacist-Patient-Oncologist Communication.

Oncology patients frequently use herbal and other forms of complementary medicine, often without the knowledge of oncologists, pharmacists, and other healthcare professionals responsible for their care. Oncology healthcare professionals may lack the knowledge needed to guide their patients on the safe and effective use of herbal medicinal products, a number of which have potentially harmful effects, which include direct toxicity and negative herb–drug interactions. The current review addresses the prevalence and expectations of oncology patients from herbal medicine, as well as evidence for the beneficial or harmful effects of this practice (potential and actual), especially when the herbal products are used in conjunction with anticancer agents. Models of integrative oncology care are described, in which open and effective communication among oncologists, pharmacists, and integrative physicians on the use of herbal medicine by their patients occurs. This collaboration provides patients with a nonjudgmental and multidisciplinary approach to integrative medicine, echoing their own health-belief models of care during conventional cancer treatments. The role of the integrative physician is to facilitate this process, working with oncologists and pharmacists in the fostering of patient-centered palliative care, while ensuring a safe and effective treatment environment. Case scenario: W. is a 56 year old female artist who was recently diagnosed with localized hormone receptor-positive breast cancer. Following lumpectomy and sentinel node dissection, she is scheduled to begin adjuvant chemotherapy with a regimen which will include adriamycin, cyclophosphamide, and paclitaxel (AC-T protocol). She is worried about developing peripheral neuropathy and its impact on her ability to paint, and she asks about a number of dietary supplements which she heard could prevent this from happening: omega-3, vitamin E, alpha-lipoic acid, and acetyl-l-carnithine. She is concerned, however, that the supplements may negatively interact with her chemotherapy regimen.

A Survey of Breast Pathologists’ Practice in Staging Multiple Foci of Invasive Carcinoma

The American Joint Committee on Cancer (AJCC) staging system is the reference standard for describing the extent of neoplastic disease on the basis of the size of primary tumor (T), and the presence of regional lymph node (N) involvement and distant metastasis (M). Multiple foci of invasive breast carcinoma may pose staging challenges to the reporting pathologist. We set out to evaluate the practice of local breast pathologists with regard to staging of multiple foci of invasive carcinoma. Breast pathologists were surveyed at a Community of Interest in Breast Pathology meeting. The live voting survey contained 6 case-based scenarios of multiple foci of invasive mammary carcinoma of the same or different histologic type and with unilateral or bilateral involvement. A supporting illustration was provided for each case. There was poor interobserver agreement with no consensus reached among the respondents in any of the cases. Staging choices varied from staging tumors together irrespective of histology or procedure type to staging tumors of the same histologic type together, or staging each tumor focus separately. Confusion was particularly evident when tumor foci with different histologic types were present. Inconsistencies exist in the reporting of AJCC pathologic TNM stage for multiple foci of invasive carcinoma. The results serve as a reminder that education and strict adherence to the AJCC guidelines is essential for establishing standard practice in order to provide accurate cancer staging and ensure optimal clinical management.

Bone Mineral Density at the Time of Initiating Aromatase Inhibitor Therapy Is Associated With Decreased Fractures in Women With Breast Cancer.

Women with estrogen receptor-positive breast cancer who receive an aromatase inhibitor (AI) are at risk for fractures. We aim to determine if dual-energy X-ray absorptiometry (DXA) scans made at the time of AI initiation are associated with decreased fractures. We retrospectively identified 25,158 women with local or regional breast cancer diagnosed between 2005 and 2013 who received AI therapy between 2007 and 2013 from the Medicare-linked Surveillance, Epidemiology, and End Results Program and Texas Cancer Registry databases. We defined baseline DXA screening using claims made between 1 year before and 6 months after each patient's first AI claim to examine determinants of baseline screening using a multivariable GENMOD model. We included a propensity score adjustment in Cox proportional hazard models to assess the association between time-varying DXA screening and the risk of fractures. Additionally, we compared the use of antiresorptive therapy drugs between the two groups. Of the study cohort, 14,738 (58.6%) received DXA screening. The screening rates increased annually from 52.1% in 2007 to 61.7% in 2013. Higher screening rates were observed in patients with younger age, married status, non-Hispanic white race, localized disease, fewer comorbidities, more than one type of aromatase inhibitor drug claim, no state buy-in (surrogate for low socioeconomic status), higher education level, and prior osteoporosis diagnosis. Baseline DXA screening was associated with decreased risk of subsequent fractures (hazard ratio=0.91; 95% confidence interval, 0.86-0.97, p < .001) after multivariable and propensity score adjustment. Bone-modifying drugs were prescribed to 4440 (30.1%) patients with screening compared with 1766 (16.9%) without (p < .001). Of the 4440 patients who received treatment, 95% received bisphosphonates. Our study demonstrated baseline DXA screening was associated with a decreased risk of fractures and a higher likelihood of receiving antiresorptive therapies. Improvement of the baseline DXA screening is still needed in practice. © 2021 American Society for Bone and Mineral Research (ASBMR).