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Background: Breast cancer development involves a series of mutations in a heterogeneous group of proto-oncogenes/tumor suppressor genes that alter mammary cells to create a microenvironment permissive to tumorigenesis. Exposure to hormones during infertility treatment may have a mutagenic effect on normal mammary epithelial cells, high-risk breast lesions and early-stage breast cancers. Our goal was to understand the association between infertility treatment and normal and cancerous breast cell proliferation.Methods: MCF-10A normal mammary cells and the breast cancer cell lines MCF-7 [estrogen receptor (ER)-positive, well differentiated] and HCC 1937 (ER-negative, aggressive, BRCA1 mutation) were treated with the weak ER activator clomiphene citrate and hormones that are increased during infertility treatment. Direct effects of treatment on cell proliferation and colony growth were determined.Results: While clomiphene citrate had no effect on MCF-10A cells or MCF-7 breast cancer cells, it decreased proliferation of HCC 1937 versus untreated cells (P= 0.003). Estrogen had no effect on either MCF-10A or HCC 1937 cells but, as expected, increased cell proliferation (20-100 nM; P≤0.002) and colony growth (10-30 nM; P< 0.0001) of MCF-7 cells versus control. Conversely, progesterone decreased both proliferation (P= 0.001) and colony growth (P= 0.01) of MCF-10A cells, inhibited colony size of MCF-7 cells (P= 0.01) and decreased proliferation of HCC 1937 cells (P= 0.008) versus control. hCG (100 mIU/ml) decreased both proliferation (P ≤ 0.01) and colony growth (P ≤ 0.002) of all three cell lines.Conclusions: Although these data are preclinical, they support possible indirect estrogenic effects of infertility regimens on ER-positive breast cancer cells and validate the potential protective effect of pregnancy-related exposure to hCG. [ABSTRACT FROM AUTHOR]

Objective: To examine the impact of hormones used for controlled ovarian hyperstimulation (COH) on normal and malignant breast cell growth and proliferation.Design: In vitro study of cultured normal and malignant breast cell lines.Setting: Academic medical center.Patient(s): None.Intervention(s): Normal and malignant breast cell lines cultured in two- and three-dimensional (2D and 3D) systems and treated with follicle-stimulating hormone (FSH), luteinizing hormone (LH), or FSH with LH or human chorionic gonadotropin (hCG).Main Outcome Measure(s): Effects of treatment on cell proliferation in 2D culture using the MTS assay and on colony growth in 3D culture.Result(s): Compared with untreated cells, normal MCF-10A cells showed a decrease in proliferation and colony size when exposed to a combination of FSH and hCG. The HCC 1937 cells treated with FSH and LH also showed a decrease in colony growth but no change in proliferation. None of the treatments had an effect on the proliferation or colony size of the MCF-7 cells.Conclusion(s): Follicle-stimulating hormone, LH, and hCG do not appear to cause an increase in cell proliferation or colony growth in either normal or malignant mammary epithelial cell lines. The potential risk for mammary cell transformation associated with these agents may be related to indirect endocrine effects on breast cell physiology. [ABSTRACT FROM AUTHOR]

Introduction: Natural killer (NK) cell-based therapies are a promising new method for treating indolent cancer, however engineering new therapies is complex and progress towards therapy for solid tumors is slow. New methods for determining the underlying intracellular signaling driving the killing phenotype would significantly improve this progress., Methods: We combined single-cell RNA sequencing with live cell imaging of a model system of NK cell killing to correlate transcriptomic data with functional output. A model of NK cell activity, the NK-92 cell line killing of HeLa cervical cancer cells, was used for these studies. NK cell killing activity was observed by microscopy during co-culture with target HeLa cells and killing activity subsequently manually mapped based on NK cell location and Annexin V expression. NK cells from this culture system were profiled by single-cell RNA sequencing using the 10× Genomics platform, and transcription factor activity inferred using the Viper and DoRothEA R packages. Luminescent microscopy of reporter constructs in the NK cells was then used to correlate activity of inferred transcriptional activity with killing activity., Results: NK cells had heterogeneous killing activity during 10 h of culture with target HeLa cells. Analysis of the single cell sequencing data identified Nuclear Factor Kappa B (NF-κB), Signal Transducer and Activator of Transcription 1 (STAT1) and MYC activity as potential drivers of NK cell functional phenotype in our model system. Live cell imaging of the transcription factor activity found NF-κB activity was significantly correlated with past killing activity. No correlation was observed between STAT1 or MYC activity and NK cell killing., Conclusions: Combining luminescent microscopy of transcription factor activity with single-cell RNA sequencing is an effective means of assigning functional phenotypes to inferred transcriptomics data., Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00812-3., Competing Interests: Competing InterestsThe authors declare no competing interests related to this work., (© The Author(s), under exclusive licence to Biomedical Engineering Society 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Antibodies to programmed cell death protein1 (anti-PD-1) have become a promising immunotherapy for triple negative breast cancer (TNBC), blocking PD-L1 signaling from pro-tumor cells through T cell PD-1 receptor binding. Nevertheless, only 10-20% of PD-L1 + metastatic TNBC patients who meet criteria benefit from ICB, and biomarkers to predict patient response have been elusive. We have previously developed an immunological niche, consisting of a microporous implant in the subcutaneous space, that supports tissue formation whose immune composition is consistent with that within vital organs. Herein, we investigated dynamic gene expression within this immunological niche to provide biomarkers of response to anti-PD-1. In a 4T1 model of metastatic TNBC, we observed sensitivity and resistance to anti-PD-1 based on primary tumor growth and survival. The niche was biopsied before, during, and after anti-PD-1 therapy, and analyzed for cell types and gene expression indicative of treatment refractivity. Myeloid cell-to-lymphocyte ratios were altered between ICB-sensitivity and resistance. Longitudinal analysis of gene expression implicated dynamic myeloid cell function that stratified sensitivity from resistance. A niche-derived gene signature predicted sensitivity or resistance prior to therapy. Analysis of the niche to monitor immunotherapy response presents a new opportunity to personalize care and investigate mechanisms underlying treatment resistance., Competing Interests: Conflict of Interest Statement: L.D.S. and J.S.J. consult and have financial interests in COUR Pharmaceutical Development, Inc.

Metastasis is the stage at which the prognosis substantially decreases for many types of cancer. The ability of tumor cells to metastasize is dependent upon the characteristics of the tumor cells, and the conditioning of distant tissues that support colonization by metastatic cells. In this report, we investigated the systemic alterations in distant tissues caused by multiple human breast cancer cell lines and the impact of these alterations on the tumor cell phenotype. We observed that the niche within the lung, a common metastatic site, was significantly altered by MDA-MB-231, MCF7, and T47 tumors, and that the lung microenvironment stimulated, to differing extents, an epithelial-to-mesenchymal transition (EMT), reducing proliferation, increasing transendothelial migration and senescence, with no significant impact on cell death. We also investigated the ability of an implantable scaffold, which supports the formation of a distant tissue, to serve as a surrogate for the lung to identify systemic alterations. The scaffolds are conditioned by the primary tumor similarly to the lung for each tumor type, evidenced by promoting a pro-EMT profile. Collectively, we demonstrate that metastatic and non-metastatic breast cancers condition distant tissues, with distinct effects on tumor cell responses, and that a surrogate tissue can distinguish the metastatic potential of human breast cancer cell lines in an accessible site that avoids biopsy of a vital organ.

Metastatic breast cancer is often not diagnosed until secondary tumors have become macroscopically visible and millions of tumor cells have invaded distant tissues. Yet, metastasis is initiated by a cascade of events leading to formation of the pre-metastatic niche, which can precede tumor formation by a matter of years. We aimed to distinguish the potential for metastatic disease from nonmetastatic disease at early times in triple-negative breast cancer using sister cell lines 4T1 (metastatic), 4T07 (invasive, nonmetastatic), and 67NR (nonmetastatic). We used a porous, polycaprolactone scaffold, that serves as an engineered metastatic niche, to identify metastatic disease through the characteristics of the microenvironment. Analysis of the immune cell composition at the scaffold was able to distinguish noninvasive 67NR tumor-bearing mice from 4T07 and 4T1 tumor-bearing mice but could not delineate metastatic potential between the two invasive cell lines. Gene expression in the scaffolds correlated with the up-regulation of cancer hallmarks (e.g., angiogenesis, hypoxia) in the 4T1 mice relative to 4T07 mice. We developed a 9-gene signature ( Dhx9 , Dusp12 , Fth1 , Ifitm1 , Ndufs1 , Pja2 , Slc1a3 , Soga1 , Spon2 ) that successfully distinguished 4T1 disease from 67NR or 4T07 disease throughout metastatic progression. Furthermore, this signature proved highly effective at distinguishing diseased lungs in publicly available datasets of mouse models of metastatic breast cancer and in human models of lung cancer. The early and accurate detection of metastatic disease that could lead to early treatment has the potential to improve patient outcomes and quality of life., Competing Interests: Lonnie D. Shea and Jacqueline S. Jeruss have pending patent applications US20170281798A1 (Northwestern University) and US2017012556 (University of Michigan) with the scaffold technology. The remaining authors have no conflicts of interest to declare., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Biomaterial scaffolds mimicking the environment in metastatic organs can deconstruct complex signals and facilitate the study of cancer progression and metastasis. Here we report that a subcutaneous scaffold implant in mouse models of metastatic breast cancer in female mice recruits lung-tropic circulating tumor cells yet suppresses their growth through potent in situ antitumor immunity. In contrast, the lung, the endogenous metastatic organ for these models, develops lethal metastases in aggressive breast cancer, with less aggressive tumor models developing dormant lungs suppressing tumor growth. Our study reveals multifaceted roles of neutrophils in regulating metastasis. Breast cancer-educated neutrophils infiltrate the scaffold implants and lungs, secreting the same signal to attract lung-tropic circulating tumor cells. Second, antitumor and pro-tumor neutrophils are selectively recruited to the dormant scaffolds and lungs, respectively, responding to distinct groups of chemoattractants to establish activated or suppressive immune environments that direct different fates of cancer cells., (© 2023. Springer Nature Limited.)

Background: Sentinel node biopsy (SLNB) is not routinely recommended for patients undergoing prophylactic mastectomy (PM), yet omission remains a subject of debate among surgeons. A modern patient cohort was examined to determine occult malignancy (OM) incidence within PM specimens to reinforce current recommendations., Methods: All PM performed over a 5-year period were retrospectively identified, including women with unilateral breast cancer who underwent synchronous or delayed contralateral PM or women with elevated cancer risk who underwent bilateral PM., Results: The study population included 772 patients (598 CPM, 174 BPM) with a total of 39 OM identified: 17 invasive cancers (14 CPM, 3 BPM) and 22 DCIS (19 CPM, 3 BPM). Of the 86 patients for whom SLNB was selectively performed, 1 micrometastasis was identified. In the CPM cohort, risk of OM increased with age, presence of LCIS of either breast, or presence of a non-BRCA high-penetrance gene mutation, while preoperative magnetic resonance imaging was associated with lower likelihood of OM., Conclusions: Given the low incidence of invasive OM in this updated series, routine SLNB is of low value for patients undergoing PM. For patients with indeterminate radiographic findings, discordant preoperative biopsies, LCIS, or non-BRCA high-penetrance gene mutations, selective SLNB implementation could be considered., (© 2022 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Microenvironmental changes in the early metastatic niche may be exploited to identify therapeutic targets to inhibit secondary tumor formation and improve disease outcomes. We dissected the developing lung metastatic niche in a model of metastatic, triple-negative breast cancer using single-cell RNA-sequencing. Lungs were extracted from mice at 7-, 14-, or 21 days after tumor inoculation corresponding to the pre-metastatic, micro-metastatic, and metastatic niche, respectively. The progression of the metastatic niche was marked by an increase in neutrophil infiltration (5% of cells at day 0 to 81% of cells at day 21) and signaling pathways corresponding to the hallmarks of cancer. Importantly, the pre-metastatic and early metastatic niche were composed of immune cells with an anti-cancer phenotype not traditionally associated with metastatic disease. As expected, the metastatic niche exhibited pro-cancer phenotypes. The transition from anti-cancer to pro-cancer phenotypes was directly associated with neutrophil and monocyte behaviors at these time points. Predicted metabolic, transcription factor, and receptor-ligand signaling suggested that changes in the neutrophils likely induced the transitions in the other immune cells. Conditioned medium generated by cells extracted from the pre-metastatic niche successfully inhibited tumor cell proliferation and migration in vitro and the in vivo depletion of pre-metastatic neutrophils and monocytes worsened survival outcomes, thus validating the anti-cancer phenotype of the developing niche. Genes associated with the early anti-cancer response could act as biomarkers that could serve as targets for the treatment of early metastatic disease. Such therapies have the potential to revolutionize clinical outcomes in metastatic breast cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Suppressive myeloid cells, including monocyte and neutrophil populations, play a vital role in the metastatic cascade and can inhibit the anti-tumor function of cytotoxic T-cells. Cargo-free polymeric nanoparticles (NPs) have been shown to modulate innate immune cell responses in multiple pathologies of aberrant inflammation. Here, we test the hypothesis that the intravenous administration of drug-free NPs in the 4T1 murine model of metastatic triple-negative breast cancer can reduce metastatic colonization of the lungs, the primary metastatic site, by targeting the pro-tumor immune cell mediators of metastatic progression. In vivo studies demonstrated that NP administration reprograms the immune milieu of the lungs and reduces pulmonary metastases. Single-cell RNA sequencing of the lungs revealed that intravenous NP administration alters myeloid cell phenotype and function, skewing populations toward inflammatory, anti-tumor phenotypes and away from pro-tumor phenotypes. Monocytes, neutrophils, and dendritic cells in the lungs of NP-treated mice upregulate gene pathways associated with IFN signaling, TNF signaling, and antigen presentation. In a T-cell deficient model, NP administration failed to abrogate pulmonary metastases, implicating the vital role of T-cells in the NP-mediated reduction of metastases. NPs delivered as an adjuvant therapy, following surgical resection of the primary tumor, led to clearance of established pulmonary metastases in all treated mice. Collectively, these results demonstrate that the in vivo administration of cargo-free NPs reprograms myeloid cell responses at the lungs and promotes the clearance of pulmonary metastases in a method of action dependent on functional T-cells., Competing Interests: Authors SK, QX, JP, TM, and AE are employees of COUR Pharmaceutical Development Co, Inc., and author LS consults and has financial interests in COUR Pharmaceutical Development, Inc. These studies were funded, in part, by COUR Pharmaceutical Development Co, Inc., which holds the intellectual property for nanoparticles studied in this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Raghani, Ma, Zhang, Orbach, Wang, Zeinali, Nagrath, Kakade, Xu, Podojil, Murthy, Elhofy, Jeruss and Shea.)

Purpose: Chemotherapy-induced alopecia (CIA) is a stigmatizing and psychologically devasting side effect of cancer treatment. Scalp cooling therapy (SCT) is the most effective method to reduce CIA, yet it is underutilized. We investigated factors that may impact scalp cooling discussion and use., Methods: We performed a retrospective review of cancer patients from 2000 to 2019 who had documentation of SCT discussion in the electronic medical record. The University of Michigan Rogel Cancer Center registry was used to identify the total number of cancer patients eligible for SCT during 2015-2019. Chi-square tests were used for outcome and patient characteristic comparisons (p < 0.05)., Results: From 2000 to 2019, 194 patients had documentation of SCT discussion. Of those, 72 (43.6%) used SCT, 93 (47.9%) did not use SCT, and the remaining 29 (17.8%) had unknown SCT use. A total of 5615 cancer patients were eligible for SCT from 2015 to 2019. As compared to those who did not have documented SCT discussions, patients who had documentation of SCT discussions in that period (n = 161, 3.0%) were more likely to be female, have breast cancer, be less than 45 years old, and live in a zip code with average income > US $100,000 (all p < 0.0001). Between 2015 and 2019, 57 patients (1.02%) used SCT. On univariate analysis, patient-initiated conversation about SCT (p = 0.01) and age less than 65 (p = 0.03) were significantly associated with decision to use SCT., Conclusion: There were distinctions in the types of patients who have documented discussions about SCT. Improving patient knowledge about the availability of SCT and increasing access to this technology for all eligible cancer patients may enable more patients to achieve improved quality of life by reducing or preventing CIA., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Given the significant benefit of targeted therapies for HER2+ breast cancer patients in both the neoadjuvant and adjuvant settings, it is critical to identify all eligible patients for these treatments. We sought to investigate cT1cN0 HER2+ patients to determine the rate of postsurgical nodal positivity, and to identify presurgical factors associated with nodal positivity. We hypothesize there is a subset of underdiagnosed HER2+ patients who would benefit from preoperative axillary imaging and inclusion in neoadjuvant chemotherapy regimens., Methods: We performed a 10-year retrospective analysis of T1 HER2+ breast cancer patients. Clinicopathologic characteristics were evaluated based on surgical nodal data., Results: We identified 38 patients with cT1cN0 HER2+ cancer. Of this cohort, 24% had positive lymph nodes on final pathology. High tumor grade (p = 0.035) on core needle biopsy and the presence of lymphovascular invasion (p = 0.0036) were associated with an increased likelihood of lymph node positivity. The majority (66%) of lymph node positive patients were clinically T1c., Conclusions: We identified a 24% nodal positivity rate in clinically node negative T1 HER2+ breast cancer patients. In particular, HER2+ patients with high-grade T1c cancers should undergo preoperative diagnostic axillary imaging to expand potential benefit from targeted therapies., (© 2022 Wiley Periodicals LLC.)

Purpose: Scalp cooling therapy (SCT) is the most effective method to reduce chemotherapy-induced alopecia (CIA), a highly distressing side effect of cancer treatment. Despite data supporting SCT efficacy and safety, SCT use in the United States is not widespread. Oncologists' interactions with scalp cooling were examined to identify facilitators and barriers to SCT implementation., Methods: A 33-question survey was distributed through the ASCO Research Survey Pool to a nationally representative, random sample of 600 oncology providers. Outcome measures included knowledge of SCT, frequency of initiating conversations about SCT with patients, degree of support, and barriers for SCT. Significance was defined as P < .001., Results: Of 155 (25.8%) responding providers, 62% of providers were in favor of SCT always or most of the time, but only 26% reported initiating discussions about SCT always or most of the time. Providers who treat breast cancer ( P ≤ .0001), those who report being very familiar with SCT ( P ≤ .0001), those who report having read SCT literature in the past 2 years ( P ≤ .0001), and those who work at a facility with machine SCT ( P ≤ .0001) were significantly more likely to initiate conversations with patients about SCT. Financial concerns (58%) were the primary reason for not recommending SCT use; efficacy (31%), staff or facility (24%), and safety (15%) concerns were also noted. Although safety concerns have decreased markedly over time, 14% of providers report patients who continue to express these concerns and 17% of providers see safety issues as barriers to supporting SCT., Conclusion: Our findings suggest that oncology provider familiarity and experience with SCT lead to increased support for scalp cooling, which may ultimately result in greater availability and utilization of SCT when indicated., Competing Interests: N. Lynn HenryResearch Funding: Pfizer, AbbVieOpen Payments Link: https://openpaymentsdata.cms.gov/physician/27894/summary Jacqueline S. JerussConsulting or Advisory Role: onCour Kelley M. KidwellHonoraria: Mallinckrodt Monika L. BurnessResearch Funding: Cyteir, Pfizer, GenentechNo other potential conflicts of interest were reported.

TGFβ signaling enacts tumor-suppressive functions in normal cells through promotion of several cell regulatory actions including cell-cycle control and apoptosis. Canonical TGFβ signaling proceeds through phosphorylation of the transcription factor, SMAD3, at the C-terminus of the protein. During oncogenic progression, this tumor suppressant phosphorylation of SMAD3 can be inhibited. Overexpression of cyclins D and E, and subsequent hyperactivation of cyclin-dependent kinases 2/4 (CDKs), are often observed in breast cancer, and have been associated with poor prognosis. The noncanonical phosphorylation of SMAD3 by CDKs 2 and 4 leads to the inhibition of tumor-suppressive function of SMAD3. As a result, CDK overactivation drives oncogenic progression, and can be targeted to improve clinical outcomes. This review focuses on breast cancer, and highlights advances in the understanding of CDK-mediated noncanonical SMAD3 phosphorylation. Specifically, the role of aberrant TGFβ signaling in oncogenic progression and treatment response will be examined to illustrate the potential for therapeutic discovery in the context of cyclins/CDKs and SMAD3.

Background: The management of clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC) has progressed with the potential to avoid the morbidity of axillary lymph node dissection in patients with complete response to therapy. This study addresses the impact of pretreatment nodal burden and tumor subtype on axillary pathologic complete response (AXpCR) in patients treated with NAC to better inform axillary surgical management., Methods: A prospective database was reviewed to identify clinically node-positive patients who underwent NAC followed by axillary lymph node dissection. Patients were stratified in accordance with abnormal nodal burden on pretreatment axillary imaging defined as low (1-2 nodes) or high (≥3 nodes), and biologic subtype defined by hormone receptor (HR+, HR-) and HER2 (human epidermal growth factor receptor 2) status. The primary outcome was AXpCR., Results: AXpCR was 43% in the study population. There was no difference in AXpCR between low and high nodal burden groups (44% versus 42%, P = 0.87). Subtype correlated to AXpCR (P < 0.001) with the highest rate (78%) in the HR-/HER2+ group. Overall, HER2+ patients had a significantly higher AXpCR than HER2- subtypes (66% versus 28% P < 0.001). HR and HER2 status were also predictive of AXpCR when comparing patient, tumor, and treatment variables., Conclusions: Biologic subtype better correlated with rates of AXpCR than nodal burden alone with the highest rates of AXpCR in HER2+ patients. Consideration of tumor biology is more informative than nodal burden when evaluating options for axillary management after NAC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Breast cancer is the most common cancer in reproductive age women, and treatment can affect fertility; however, there is often concern regarding the safety of increased estradiol (E 2 ) levels and potential delays in treatment with ovarian stimulation for fertility preservation (FP). The aim of this study was to compare recurrence and survival in breast cancer patients who pursued FP without concurrent letrozole to those who did not (non-FP)., Methods: We reviewed charts of women with breast cancer who contacted the FP patient navigator (PN) at Northwestern University from 01/2005-01/2018. Oncology and fertility outcome data were collected. Data were analyzed by Chi-square test or regression, as appropriate. Kaplan-Meier curves were used to examine breast cancer recurrence and survival. Statistical analyses were performed with SPSS IBM Statistics 26.0 for Windows., Results: 332 patients were included, of which 157 (47.3%) underwent FP. Median days to treatment after consulting the PN was 35 in the FP group and 21 in non-FP (p < 0.05). Cancer recurrence was noted in 7 (4.7%) FP patients and 13 (7.9%) non-FP patients (NS), and mortality in 5 (3.2%) FP patients and 7 (4.2%) non-FP patients (NS). Within the FP group, no significant differences were found in recurrence or mortality based on ER status, age, BMI, peak E 2 level or total gonadotropin dose. Likelihood of pursuing FP was primarily a function of age and parity, and was not affected by breast cancer stage. To date, 21 have used cryopreserved specimens, and 13 (62%) had a live birth., Conclusions: FP is safe and effective in breast cancer patients, regardless of receptor status; E 2 elevations and the 2-week delay in treatment start are unlikely to be clinically significant. These findings are unique in that our institution does not use concomitant letrozole during stimulation to minimize E 2 elevations in breast cancer patients.

Pancreatic cancer has the worst prognosis of all cancers due to disease aggressiveness and paucity of early detection platforms. We developed biomaterial scaffolds that recruit metastatic tumor cells and reflect the immune dysregulation of native metastatic sites. While this platform has shown promise in orthotopic breast cancer models, its potential in other models is untested. Herein, we demonstrate that scaffolds recruit disseminated pancreatic cells in the KPCY model of spontaneous pancreatic cancer prior to adenocarcinoma formation (3-fold increase in scaffold YFP + cells). Furthermore, immune cells at the scaffolds differentiate early- and late-stage disease with greater accuracy (0.83) than the natural metastatic site (liver, 0.50). Early disease was identified by an approximately 2-fold increase in monocytes. Late-stage disease was marked by a 1.5-2-fold increase in T cells and natural killer cells. The differential immune response indicated that the scaffolds could distinguish spontaneous pancreatic cancer from spontaneous breast cancer. Collectively, our findings demonstrate the utility of scaffolds to reflect immunomodulation in two spontaneous models of tumorigenesis, and their particular utility for identifying early disease stages in the aggressive KPCY pancreatic cancer model. Such scaffolds may serve as a platform for early detection of pancreatic cancer to improve treatment and prognosis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Guidelines allow for the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy in women ≥ 70 years of age with hormone receptor-positive (HR +) breast cancer. Despite this, national data suggest these procedures have not been widely de-implemented., Objectives: Our objectives were to evaluate trends in SLNB and post-lumpectomy radiotherapy utilization in patients who are eligible for omission, and evaluate patient preferences as a target for de-implementation of low-value care., Methods: We performed a sequential explanatory mixed-methods study by first analyzing an institutional database of patients ≥ 70 years of age with HR + breast cancer who received surgical treatment from 2014 to 2018. Based on the quantitative data, we conducted semi-structured interviews with women identified as high or low utilizers of breast cancer treatments to elicit patient perspectives on de-implementation., Results: SLNB and post-lumpectomy radiotherapy were performed in 68% and 43% of patients, respectively, who met the criteria for omission. There was a significant decrease in SLNB rates from 2014 to 2018. Forty-nine percent of patients were classified as high utilizers and 26% were classified as low utilizers. Qualitative analysis found that the most important factors influencing decision making regarding SLNB and post-lumpectomy radiotherapy omission for both high and low utilizers were trust in their provider and a desire for peace of mind., Conclusions: Despite efforts to de-implement low-value care, older women with HR + breast cancer remain at risk of overtreatment. Patient perspectives suggest that multi-level de-implementation strategies will need to target provider practice patterns and patient-provider communication to promote high-quality decision making and reduction in breast cancer overtreatment.

The presence of immunosuppressive innate immune cells such as myeloid derived suppressor cells (MDSCs), Ly6C-high monocytes, and tumor-associated macrophages (TAMs) at a tumor can inhibit effector T cell and NK cell function. Immune checkpoint blockade using anti-PD-1 antibody aims to overcome the immune suppressive environment, yet only a fraction of patients responds. Herein, we test the hypothesis that cargo-free PLG nanoparticles administered intravenously can divert circulating immune cells from the tumor microenvironment to enhance the efficacy of anti-PD-1 immunotherapy in the 4T1 mouse model of metastatic triple-negative breast cancer. In vitro studies demonstrate that these nanoparticles decrease the expression of MCP-1 by 5-fold and increase the expression of TNF-α by more than 2-fold upon uptake by innate immune cells. Intravenous administration of particles results in internalization by MDSCs and monocytes, with particles detected in the liver, lung, spleen, and primary tumor. Nanoparticle delivery decreased the abundance of MDSCs in circulation and in the lung, the latter being the primary metastatic site. Combined with anti-PD-1 antibody, nanoparticles significantly slowed tumor growth and resulted in a survival benefit. Gene expression analysis by GSEA indicated inflammatory myeloid cell pathways were downregulated in the lung and upregulated in the spleen and tumor. Upregulation of extrinsic apoptotic pathways was also observed in the primary tumor. Collectively, these results demonstrate that cargo-free PLG nanoparticles can reprogram immune cell responses and alter the tumor microenvironment in vivo to overcome the local immune suppression attributed to myeloid cells and enhance the efficacy of anti-PD-1 therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium., Methods: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process., Results: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity., Conclusion: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

Rationale and Objectives: To assess for indirect evidence of gadoteridol retention in the deep brain nuclei of women undergoing serial screening breast MRI., Methods: This HIPAA-compliant prospective observational noninferiority imaging trial was approved by the IRB. From December 2016 to March 2018, 12 consented subjects previously exposed to 0-1 doses of gadoteridol (group 1) and 7 consented subjects previously exposed to ≥4 doses of gadoteridol (group 2) prospectively underwent research-specific unenhanced brain MRI including T1w spin echo imaging and T1 mapping. Inclusion criteria were: (1) planned breast MRI with gadoteridol, (2) no gadolinium exposure other than gadoteridol, (3) able to undergo MRI, (4) no neurological illness, (5) no metastatic disease, (6) no chemotherapy. Regions of interest were manually drawn in the globus pallidus, thalamus, dentate nucleus, and pons. Globus pallidus/thalamus and dentate nucleus/pons signal intensities and T1-time ratios were calculated using established methods and correlated with cumulative gadoteridol dose (mL)., Results: All subjects were female (mean age: 50 ± 12 years) and previously had received an average of 0.5 ± 0.5 (group 1) and 5.9 ± 2.1 (group 2) doses of gadoteridol (cumulative dose: 8 ± 8 and 82 ± 31 mL, respectively), with the last dose an average of 492 ± 299 days prior to scanning. There was no significant correlation between cumulative gadoteridol dose (mL) and deep brain nuclei signal intensity at T1w spin echo imaging (p = 0.365-0.512) or T1 mapping (p = 0.197-0.965)., Conclusion: We observed no indirect evidence of gadolinium retention in the deep brain nuclei of women undergoing screening breast MRI with gadoteridol., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

The efficacy of trastuzumab, a treatment for HER2+ breast cancer, can be limited by the development of resistance. Cyclin E (CCNE) overexpression has been implicated in trastuzumab resistance. We sought to uncover a potential mechanism for this trastuzumab resistance and focused on a model of CCNE overexpressing HER2+ breast cancer and noncanonical phosphorylation of the TGF-β signaling protein, SMAD3. Network analysis of transcriptional activity in a HER2+, CCNE overexpressing, trastuzumab-resistant cell line (BT474R2) identified decreased SMAD3 activity was associated with treatment resistance. Immunoblotting showed SMAD3 expression was significantly downregulated in BT474R2 cells ( p < .01), and noncanonical phosphorylation of SMAD3 was increased in these CCNE-overexpressing cells. Also, in response to CDK2 inhibition, expression patterns linked to restored canonical SMAD3 signaling, including decreased cMyc and increased cyclin-dependent inhibitor, p15, were identified. The BT474R2 cell line was modified through overexpression of SMAD3 (BT474R2-SMAD3), a mutant construct resistant to CCNE-mediated noncanonical phosphorylation of SMAD3 (BT474R2-5M), and a control (BT474R2-Blank). In vitro studies examining the response to trastuzumab showed increased sensitivity to treatment for BT474R2-5M cells. These findings were then validated in NSG mice inoculated with BT474R2-5M cells or BT474R2 control cells. After treatment with trastuzumab, the NSG mice inoculated with BT474R2-5M cells developed significantly lower tumor volumes ( p < .001), when compared to mice inoculated with BT474R2 cells. Taken together, these results indicate that for patients with HER2+ breast cancer, a mechanism of CCNE-mediated trastuzumab resistance, regulated through noncanonical SMAD3 phosphorylation, could be treated with CDK2 inhibition to help enhance the efficacy of trastuzumab therapy.

Cancer metastasis poses a challenging problem both clinically and scientifically, as the stochastic nature of metastatic lesion formation introduces complexity for both early detection and the study of metastasis in preclinical models. Engineered metastatic niches represent an emerging approach to address this stochasticity by creating bioengineered sites where cancer can preferentially metastasize. As the engineered niche captures the earliest metastatic cells at a nonvital location, both noninvasive and biopsy-based monitoring of these sites can be performed routinely to detect metastasis early and monitor alterations in the forming metastatic niche. The engineered metastatic niche also provides a new platform technology that serves as a tunable site to molecularly dissect metastatic disease mechanisms. Ultimately, linking the engineered niches with advances in sensor development and synthetic biology can provide enabling tools for preclinical cancer models and fosters the potential to impact the future of clinical cancer care., (©2020 American Association for Cancer Research.)

We sought to identify factors associated with disparities in tamoxifen utilization among young patients at high-risk for developing breast cancer. We identified 67 premenopausal, high-risk women age 35-45, without surgical prophylaxis, who did not initiate tamoxifen. Factors associated with noninitiation were examined. About 37% of patients had no documented provider-based discussion regarding initiation. Type of high-risk diagnosis was the only factor associated with a provider-based discussion (P = .03). For patients offered tamoxifen, primary reasons for noninitiation were perceived minimal benefit (66.7%), fertility concerns (16.7%), and concerns about side effects (7.1%). Implementation of comprehensive educational strategies regarding the benefits of tamoxifen should be facilitated to improve initiation among young high-risk patients., (© 2019 Wiley Periodicals, Inc.)

Monitoring metastatic events in distal tissues is challenged by their sporadic occurrence in obscure and inaccessible locations within these vital organs. A synthetic biomaterial scaffold can function as a synthetic metastatic niche to reveal the nature of these distal sites. These implanted scaffolds promote tissue ingrowth, which upon cancer initiation is transformed into a metastatic niche that captures aggressive circulating tumor cells. We hypothesized that immune cell phenotypes at synthetic niches reflect the immunosuppressive conditioning within a host that contributes to metastatic cell recruitment and can identify disease progression and response to therapy. We analyzed the expression of 632 immune-centric genes in tissue biopsied from implants at weekly intervals following inoculation. Specific immune populations within implants were then analyzed by single-cell RNA-seq. Dynamic gene expression profiles in innate cells, such as myeloid-derived suppressor cells, macrophages, and dendritic cells, suggest the development of an immunosuppressive microenvironment. These dynamics in immune phenotypes at implants was analogous to that in the diseased lung and had distinct dynamics compared with blood leukocytes. Following a therapeutic excision of the primary tumor, longitudinal tracking of immune phenotypes at the implant in individual mice showed an initial response to therapy, which over time differentiated recurrence versus survival. Collectively, the microenvironment at the synthetic niche acts as a sentinel by reflecting both progression and regression of disease. SIGNIFICANCE: Immune dynamics at biomaterial implants, functioning as a synthetic metastatic niche, provides unique information that correlates with disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/3/602/F1.large.jpg. See related commentary by Wolf and Elisseeff, p. 377 ., (©2019 American Association for Cancer Research.)

For most cancers, metastasis is the point at which disease is no longer curable. Earlier detection of metastasis, when it is undetectable by current clinical methods, may enable better outcomes. We have developed a biomaterial implant that recruits metastatic cancer cells in mouse models of breast cancer. Here, we investigate spectral ultrasound imaging (SUSI) as a non-invasive strategy for detecting metastasis to the implanted biomaterial scaffolds. Our results show that SUSI, which detects parameters related to tissue composition and structure, identified changes at an early time point when tumor cells were recruited to scaffolds in orthotopic breast cancer mouse models. These changes were not associated with acellular components in the scaffolds but were reflected in the cellular composition in the scaffold microenvironment, including an increase in CD31 + CD45-endothelial cell number in tumor bearing mice. In addition, we built a classification model based on changes in SUSI parameters from scaffold measurements to stratify tumor free and tumor bearing status. Combination of a linear discriminant analysis and bagged decision trees model resulted in an area under the curve of 0.92 for receiver operating characteristics analysis. With the potential for early non-invasive detection, SUSI could facilitate clinical translation of the scaffolds for monitoring metastatic disease.

Metastases are preceded by stochastic formation of a hospitable microenvironment known as the premetastatic niche, which has been difficult to study. Herein, we employ implantable polycaprolactone scaffolds as an engineered premetastatic niche to independently investigate the role of interleukin-10 (IL10), CXCL12, and CCL2 in recruiting immune and tumor cells and impacting breast cancer cell phenotype via lentiviral overexpression. Lentivirus delivered from scaffolds in vivo achieved sustained transgene expression for 56 days. IL10 lentiviral expression, but not CXCL12 or CCL2, significantly decreased tumor cell recruitment to scaffolds in vivo. Delivery of CXCL12 enhanced CD45+ immune cell recruitment to scaffolds while delivery of IL10 reduced immune cell recruitment. CCL2 did not alter immune cell recruitment. Tumor cell phenotype was investigated using conditioned media from immunomodulated scaffolds, with CXCL12 microenvironments reducing proliferation, and IL10 microenvironments enhancing proliferation. Migration was enhanced with CCL2 and reduced with IL10-driven microenvironments. Multiple linear regression identified populations of immune cells associated with tumor cell abundance. CD45+ immune and CD8+ T cells were associated with reduced tumor cell abundance, while CD11b+Gr1+ neutrophils and CD4+ T cells were associated with enhanced tumor cell abundance. Collectively, biomaterial scaffolds provide a tool to probe the formation and function of the premetastatic niche., (© 2019 Wiley Periodicals, Inc.)

Metastasis represents the greatest challenge to treatment of cancer patients. Biomaterial scaffolds that recruit tumor cells to a defined site in vivo are an emerging platform for the diagnosis, treatment, and study of metastasis. Recruitment of immune cells and metastatic tumor cells to a defined location provides a precision health platform to assess current clinical cancer biomarkers in a metastatic setting, and to define the next generation of biomarkers. These platforms represent an opportunity to create a molecular staging of metastasis that could aid in both the early diagnosis and treatment of metastasis., Competing Interests: CONFLICTS OF INTEREST The scaffold as a platform for metastasis detection is described in a current patent application US20170281798A1 by assignee Northwestern University with inventors Lonnie D. Shea, Samira M. Azarin, Robert M. Gower, Jacqueline S. Jeruss and US2017012556 by assignee Regents of the University of Michigan with inventors Lonnie D. Shea, Shreyas S. Rao, Samira M. Azarin, Jacqueline S. Jeruss, and Grace G. Bushnell., (Copyright: © 2019 Bushnell et al.)

Background: Sentinel lymph node biopsy (SLNB) is increasingly utilized after neoadjuvant chemotherapy (NAC) in responsive adenopathy, particularly with placement of a marking clip in the involved node(s). This may allow a subset of patients to avoid axillary lymph node dissection. SLNB is still discouraged in inflammatory breast cancer (IBC). The purpose of this study is to examine the axillary pathologic complete response (AXpCR) in IBC patients with clinical adenopathy. There may be an implication to approach a subset of IBC patients for SLNB after NAC., Methods: A single-institution institutional review board-approved database was reviewed. Inclusion criteria were clinicopathologic diagnosis of IBC and age ≥ 18 years. Stage IV disease was excluded. We collected data on demographics, tumor characteristics including histology and subtype, axillary status, and treatment effect details., Results: Sixty-six patients fulfilled criteria. Mean follow-up was 4.1 years. The AXpCR was 6% for luminal A and luminal B [human epidermal growth factor receptor (HER)2 -] subtypes, and 24% for basal subtype. The AXpCR rate was 64% for HER2-enriched and luminal B (HER2 +) patients. Achievement of AXpCR among these HER2-positive patients was statistically significant (p = 0.0001). There was minimal difference in achieving AXpCR in HER2-overexpressing patients regardless of hormone receptor status (p = 1.000)., Conclusions: Understanding the best patients to select for use of SLNB or targeted lymph node dissection after treatment is evolving. This unique series identified and described the axillary pathologic characteristics of IBC patients following NAC. Further research is needed to confirm that the approach, axillary node clip placement prior to treatment, is feasible and accurate in IBC.

Background: Breast cancer is the most common malignancy diagnosed in women of childbearing age. A breast cancer diagnosis in this young patient population can be uniquely complex to navigate when considering the potential impact of fertility loss associated with specific gonadotoxic therapies. Another unique challenge for young breast cancer patients is pregnancy-associated breast cancer (PABC), which occurs in approximately 1 of every 3000 pregnancies. Pregnancy adds a layer of complexity to breast cancer treatment planning as many therapies can affect the developing fetus. These two clinical challenges require nuanced multidisciplinary approaches to facilitate optimal treatment outcomes. We sought to review and summarize the management strategy options for both fertility preservation and PABC., Methods: A guideline and literature review was performed for fertility preservation, young patients with breast cancer, and pregnancy-associated breast cancer., Results: Fertility preservation options, both established and experimental, are detailed. Suggested clinical practice guidelines for PABC are also presented, which delineate breast cancer treatment recommendations based on pregnancy trimester., Conclusion: A multidisciplinary approach to patient care, including oncologists and early referral to reproductive specialists, can provide young breast cancer patients with options for fertility preservation. Under the guidance of a multidisciplinary treatment team, PABC can also be diagnosed and treated to permit the best possible outcomes for the mother and the developing fetus.

For most cancers, metastasis is the point at which clinical treatment shifts from curative intent to extending survival. Biomaterial implants acting as a synthetic premetastatic niche recruit metastatic cancer cells and provide a survival advantage, and their use as a diagnostic platform requires assessing their relevance to disease progression. Here, we showed that scaffold-captured tumor cells (SCAF) were 30 times more metastatic to the lung than primary tumor (PT) cells, similar to cells derived from lung micrometastases (LUNG). SCAF cells were more aggressive in vitro , demonstrated higher levels of migration, invasion, and mammosphere formation, and had a greater proportion of cancer stem cells than PT. SCAF cells were highly enriched for gene expression signatures associated with metastasis and had associated genomic structural changes, including globally enhanced entropy. Collectively, our findings demonstrate that SCAF cells are distinct from PT and more closely resemble LUNG, indicating that tumor cells retrieved from scaffolds are reflective of cells at metastatic sites. SIGNIFICANCE: These findings suggest that metastatic tumor cells captured by a biomaterial scaffold may serve as a diagnostic for molecular staging of metastasis. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/2042/F1.large.jpg., (©2019 American Association for Cancer Research.)

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.