Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy.

BACKGROUND: Endocrine resistant metastatic disease develops in ~ 20-25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. METHODS: This was a single arm, interventional phase II clinical trial evaluating 4 weeks (± 1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET. RESULTS: Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. CONCLUSION: Short-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. CLINICAL TRIAL REGISTRY: Trial registration number: NCT03219476.

Every Day Counts: a randomized pilot lifestyle intervention for women with metastatic breast cancer.

PURPOSE: To explore the feasibility, adherence, safety and potential efficacy of Every Day Counts; a randomized pilot trial designed for women with metastatic breast cancer (MBC) framed by the American Cancer Society nutrition and physical activity (PA) guidelines METHODS: Women with clinically stable MBC were recruited to complete an interview, dual energy X-ray absorptiometry imaging and phlebotomy at baseline and post-intervention. Multidimensional quality of life, symptom burden, lifestyle behaviors (nutrition and PA) and biomarkers of prognosis were procured and quantified. Women were randomized to the immediate intervention or a waitlist control arm. The 12-week intervention included a curriculum binder, lifestyle coaching (in-person and telephone-based sessions) and intervention support (activity monitor, text messaging, cooking classes.) Women in the waitlist control were provided monthly text messaging. RESULTS: Forty women were recruited within 9 months (feasibility). Women in the immediate intervention attended 86% of all 12 weekly coaching sessions (adherence) and showed significant improvements in general QOL (p = 0.001), and QOL related to breast cancer (p = 0.001), endocrine symptoms (p = 0.002) and fatigue (p = 0.037), whereas the waitlist control did not (all p values ≥ 0.05) (efficacy). PA significantly increased for women in the intervention compared to control (p < 0.0001), while dietary changes were less evident across groups due to high baseline adherence. No significant changes in biomarkers or lean mass were noted, yet visceral adipose tissue declined (p = 0.001). No intervention-related injuries were reported (safety). Qualitative feedback strongly supports the desire for a longer intervention with additional support. CONCLUSIONS: Lifestyle interventions are of interest, safe and potentially beneficial for women with MBC. A larger trial is warranted.

A high mitotic score in breast cancer after neoadjuvant chemotherapy is predictive of outcome and associated with a distinct morphology.

AIMS: Neoadjuvant chemotherapy (NAC) is frequently used for the treatment of breast cancer. We sought to analyse the clinical, morphological and immunohistochemical features of tumours from patients who did not achieve pathological complete response following NAC. METHODS AND RESULTS: We identified stage I-III post-NAC breast cancers from surgical resections (2000-2016) with evaluable residual invasive carcinoma [ypT1a(m) or greater and ≥15% tumour cellularity]. One hundred and forty-three tumours from 142 patients were included. On univariable analysis, a high (score 3) post-NAC mitotic score (as compared with 1 or 2) was significantly associated with invasive ductal carcinoma (IDC) subtype (P = 0.023), high grade, pushing borders with zones of necrosis, hormone receptor and triple-negative status, lack of hormonal therapy, higher cellularity (P < 0.001), and a higher percentage of tumour-infiltrating lymphocytes (P = 0.016). Multivariable analysis showed a high post-NAC mitotic score to be significantly associated with recurrence, distant metastasis, and shortened survival (hazard ratios of 5.73, 4.49, and 3.68, respectively). High post-NAC mitotic score tumours (n = 32) were IDC and had a high Ki67 proliferation index (median, 55%). Of these, 24 (75%) had pushing borders with zones of necrosis; 19 (79.2%) of these had necrosis on preoperative imaging, and 24 (75%), 15 (46.9%) and four (12.5%) lacked androgen receptor, GATA-3 and cytokeratin 18 expression, respectively. CONCLUSIONS: High post-NAC mitotic score breast cancers cause high morbidity and mortality, frequently have pushing borders and zones of necrosis, and may show loss of common 'breast cancer markers'. Our findings support that necrosis in pretreatment studies and post-NAC mitotic score should be routinely reported, as they offer significant additional prognostic information to guide management.

Does Progesterone Receptor Matter in the Risk of Recurrence for Patients With Ductal Carcinoma in Situ?

BACKGROUND: Local recurrence is a major concern in patients diagnosed with ductal carcinoma in situ (DCIS). In invasive breast cancers, estrogen receptor (ER) (+)/progesterone receptor (PR) (-) subtype is considered more aggressive with poorer prognosis as compared to ER+/PR+ tumors. It is unclear whether this holds true in DCIS. METHODS: Six hundred ninety-three patients diagnosed and treated for DCIS at Froedtert and Medical College of Wisconsin Cancer Center (February 2002 to March 2015) were studied to determine if the recurrence rates were significantly different between ER+/PR- and ER+/PR+ tumors. Recurrence was defined as either noninvasive or invasive ipsilateral, contralateral, or distant disease. Probabilities of recurrences were calculated using Kaplan-Meier estimator. Cox proportional hazards model was used to evaluate the effect of prognostic factors on DCIS recurrence. RESULTS: Median follow-up was 5.2 years. The 5-year recurrence-free survival (RFS) was 91% (95% CI, 88.2-93.3) while estimated 7-year RFS was 86% (95% CI, 81.9-89.2). Seventy-five patients had a recurrence during their follow-up. Patients with ER-/PR- tumors (n = 118) had a significantly higher risk of recurrence (Hazard Ratio 3.7, 95% CI, 1.9-7.2, P = 0.0001) whereas those with ER+/PR- subtype (n = 77) did not have a significant difference in recurrence risk (HR 1.75, 95% CI, 0.92-3.32, P = 0.085) when compared to ER+/PR+ tumors (n = 482). No endocrine therapy for ER+ DCIS and lumpectomy alone were also significant predictors of recurrence (P = 0.0073 and P = 0.005, respectively). CONCLUSIONS: ER+/PR- subtype was not a significant predictor of recurrence in DCIS patients. This finding is in contrast to the recurrence risk seen in invasive breast cancers. Mastectomy and postlumpectomy radiation were associated with improved outcomes as was adjuvant endocrine therapy.

Gallium and its competing roles with iron in biological systems.

Gallium, a group IIIa metal, shares chemical properties with iron. Studies have shown that gallium-based compounds have potential therapeutic activity against certain cancers and infectious microorganisms. By functioning as an iron mimetic, gallium perturbs iron-dependent proliferation processes in tumor cells. Gallium's action on iron homeostasis leads to disruption of ribonucleotide reductase, mitochondrial function, and the regulation of transferrin receptor and ferritin. In addition, gallium nitrate stimulates an increase in mitochondrial reactive oxygen species in cells which triggers downstream upregulation of metallothionein and hemoxygenase-1. Gallium's anti-infective activity against bacteria and fungi results from disruption of microbial iron utilization through mechanisms which include gallium binding to siderophores and downregulation of bacterial iron uptake. Gallium compounds lack cross-resistance to conventional chemotherapeutic drugs and antibiotics thus making them attractive agents for drug development. This review will focus on the mechanisms of action of gallium with emphasis on its interaction with iron and iron proteins.

The therapeutic potential of iron-targeting gallium compounds in human disease: From basic research to clinical application.

Gallium, group IIIa metal, shares certain chemical characteristics with iron which enable it to function as an iron mimetic that can disrupt iron-dependent tumor cell growth. Gallium may also display antimicrobial activity by disrupting iron homeostasis in certain bacteria and fungi. Gallium's action on iron homeostasis leads to inhibition of ribonucleotide reductase, mitochondrial function, and changes in proteins of iron transport and storage. In addition, gallium induces an increase in mitochondrial reactive oxygen species in cells which triggers downstream upregulation of metallothionein and hemoxygenase-1. Early clinical trials evaluated the efficacy of the simple gallium salts, gallium nitrate and gallium chloride. However, newer gallium-ligands such as Tris(8-quinolinolato)gallium(III) (KP46) and gallium maltolate have been developed and are undergoing clinical evaluation. Additional gallium-ligands that demonstrate antitumor activity in preclinical studies have emerged. Their mechanisms of action and their spectrum of antitumor activity may extend beyond the earlier generations of gallium compounds and warrant further investigation. This review will focus on the evolution and potential of gallium-based therapeutics.

p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion.

Triple-negative breast cancer (TNBC) is highly progressive and lacks established therapeutic targets. p38γ mitogen-activated protein kinase (MAPK) (gene name: MAPK12) is overexpressed in TNBC but how overexpressed p38γ contributes to TNBC remains unknown. Here, we show that p38γ activation promotes TNBC development and progression by stimulating cancer stem-like cell (CSC) expansion and may serve as a novel therapeutic target. p38γ silencing in TNBC cells reduces mammosphere formation and decreases expression levels of CSC drivers including Nanog, Oct3/4, and Sox2. Moreover, p38γ MAPK-forced expression alone is sufficient to stimulate CSC expansion and to induce epithelial cell transformation in vitro and in vivo. Furthermore, p38γ depends on its activity to stimulate CSC expansion and breast cancer progression, indicating a therapeutic opportunity by application of its pharmacological inhibitor. Indeed, the non-toxic p38γ specific pharmacological inhibitor pirfenidone selectively inhibits TNBC growth in vitro and/or in vivo and significantly decreases the CSC population. Mechanistically, p38γ stimulates Nanog transcription through c-Jun/AP-1 via a multi-protein complex formation. These results together demonstrate that p38γ can drive TNBC development and progression and may be a novel therapeutic target for TNBC by stimulating CSC expansion. Inhibiting p38γ activity with pirfenidone may be a novel strategy for the treatment of TNBC.

Impact of obesity and exercise on chemotherapy-related fatigue.

INTRODUCTION: Breast cancer patients undergoing adjuvant chemotherapy often develop fatigue from their treatment that may persist for months. While the positive effects of physical activity in cancer patients are increasingly recognized, the impact of obesity on chemotherapy-induced fatigue has not been well studied. METHODS: Female age 35-75 years with stage I-III breast cancer receiving adjuvant chemotherapy were enrolled in an IRB-approved study. Patient fatigue was self-reported using a 14-question fatigue symptom inventory. Patients were queried about fatigue and their level of exercise before, during, and after completion of chemotherapy. BMI was measured prior to their first cycle of chemotherapy. RESULTS: Of the 47 evaluable patients, 37 reported performing exercise on a regular basis. Following chemotherapy, 53 % of the exercise group and 80 % of the non-exercise group displayed a worsening of their FS. In patients with a BMI < 25, the fatigue score (FS) after chemotherapy was 27.6 in the exercise group versus 40.5 in the non-exercise group. In patients with a BMI > 25, the FS after chemotherapy was 25.96 in the exercise group versus 32.6 in the non-exercise group. CONCLUSION: Our study indicates a trend towards fatigue reduction with exercise even in patients who are overweight. Thus, an elevated BMI at diagnosis does not preclude a breast cancer patient from experiencing the same positive effects from exercise on chemotherapy-related fatigue as patients with normal BMIs. This indicates an important role of physicians in the primary care setting to encourage patients to initiate physical activity when offering cancer-screening services.

Stay on Track: A Pilot Randomized Control Trial on the Feasibility of a Diet and Exercise Intervention in Patients with Breast Cancer Receiving Radiotherapy.

PURPOSE: Among patients with breast cancer undergoing radiotherapy, posttreatment cardiovascular disease and worsened quality of life (QoL) are leading causes of morbidity and mortality. To overcome these negative radiotherapy effects, this prospective, randomized clinical trial pilots a 12-week Stay on Track exercise and diet intervention for overweight patients with nonmetastatic breast cancer undergoing whole-breast radiotherapy. EXPERIMENTAL DESIGN: The intervention group (n = 22) participated in three personal exercise and dietary counseling sessions, and received three text reminders/week to adhere to recommendations. The control group (n = 22) was administered a diet/exercise information binder. All patients received a Fitbit, and at baseline, 3 months, and 6 months, measurements of biomarkers, dual-energy X-ray absorptiometry scans, QoL and physical activity surveys, and food frequency questionnaires were obtained. A satisfaction survey was administered at 3 months. RESULTS: Stay on Track was well received, with high rates of adherence and satisfaction. The intervention group showed an increase in self-reported physical activity and preserved QoL, a decrease in body mass index and visceral fat, and higher American Cancer Society/American Institute of Cancer Research dietary adherence. The control participants had reduced QoL, anti-inflammatory markers, and increased metabolic syndrome markers. Both groups had decreased overall body mass. These changes were within group effects. When comparing the intervention and control groups over time, there were notable improvements in dietary adherence in the intervention group. CONCLUSIONS: Targeted lifestyle interventions during radiotherapy are feasible and could decrease cardiovascular comorbidities in patients with breast cancer. Larger-scale implementation with longer follow-up can better determine interventions that influence cardiometabolic health and QoL. SIGNIFICANCE: This pilot study examines cardiometabolic benefits of a combined diet and exercise intervention for patients with breast cancer undergoing radiotherapy. The intervention included an activity tracker (FitBit) and text message reminders to promote adherence to lifestyle interventions. Large-scale implementation of such programs may improve cardiometabolic outcomes and overall QoL among patients with breast cancer.

Divergent Cellular Expression Patterns of PD-L1 and PD-L2 Proteins in Breast Cancer.

PD-L1 immunohistochemistry (IHC) has become an established method for predicting cancer response to targeted anti-PD1 immunotherapies, including breast cancer (BC). The alternative PD-1 ligand, PD-L2, remains understudied but may be a complementary predictive marker. Prospective analysis of 32 breast cancers revealed divergent expression patterns of PD-L1 and PD-L2. PD-L1-positivity was higher in immune cells than in cancer cells (median = 5.0% vs. 0.0%; p = 0.001), whereas PD-L2-positivity was higher in cancer cells than immune cells (median = 30% vs. 5.0%; p = 0.001). Percent positivity of PD-L1 and PD-L2 were not correlated, neither in cancer cells nor immune cells. Based on a cut-point of ≥1% positivity, ER+ tumors (n = 23) were frequently PD-L2-positive (73.9%), whereas only 40.9% were PD-L1-positive. These data suggest differential control of cellular PD-L1 and PD-L2 expression in BC and a potential role for PD-L2 IHC as a complementary marker to PD-L1 to improve selection of aggressive ER+ BC that may benefit from anti-PD-1 therapy.

p38γ mitogen-activated protein kinase (MAPK) confers breast cancer hormone sensitivity by switching estrogen receptor (ER) signaling from classical to nonclassical pathway via stimulating ER phosphorylation and c-Jun transcription.

Estrogen receptor (ER) α promotes breast cancer growth by regulating gene expression through classical estrogen response element (ERE) binding and nonclassical (interaction with c-Jun at AP-1 sites) pathways. ER is the target for anti-estrogens such as tamoxifen (TAM). However, the potential for classical versus nonclassical ER signaling to influence hormone sensitivity is not known. Moreover, anti-estrogens frequently activate several signaling cascades besides the target ER, and the implications of these "off-target" signaling events have not been explored. Here, we report that p38γ MAPK is selectively activated by treatment with TAM. This results in both phosphorylation of ER at Ser-118 and stimulation of c-Jun transcription, thus switching ER signaling from the classical to the nonclassical pathway leading to increased hormone sensitivity. Unexpectedly, phosphorylation at Ser-118 is required for ER to bind both p38γ and c-Jun, thereby promoting ER relocation from ERE to AP-1 promoter sites. Thus, ER/Ser-118 phosphorylation serves as a central mechanism by which p38γ regulates signaling transduction of ER with its inhibitor TAM.

Matched Case Control Analysis of Breast Cancer- Specific Factors Affecting Risk of Developing SARS-CoV-2 Infection.

INTRODUCTION: In this retrospective matched case control study, we aim to identify breast cancer-related risk factors associated with developing COVID-19 and describe outcomes of patients with breast cancer diagnosed with COVID-19. METHODS: Women with breast cancer treated at the Medical College of Wisconsin and diagnosed with COVID-19 from March through December 2020 served as cases, and those without COVID-19 within the same timeframe served as controls. Univariate and multivariate comparisons were performed. RESULTS: Twenty-five cases and 77 controls were identified. All cases were fully matched by age, obesity, county, and race. Mean age was 54.6 versus 54.9, body mass index 31.0 versus 31.6, 48% lived in Milwaukee County, and 68% were White. Regarding COVID-19 outcomes, 24.0% (n = 6) of cases were hospitalized, median length of stay was 2 days, 8% (n=2) needed oxygen, 4% (n = 6) were intubated, and 4% (n = 6) died. COVID-19 led to treatment delays in 40% of cases. On univariate analysis, there was no statistically significant difference in hormone receptor status or breast cancer stage. Being on active chemotherapy (OR 5.8, P = 0.043) significantly increased the likelihood of developing COVID-19. CONCLUSIONS: In this matched case control study of patients with breast cancer, active chemotherapy was significantly associated with an increased likelihood of developing COVID-19, with a trend seen for triple negative disease. These findings support continued strict precautions for those on active chemotherapy and warrant further analysis in those with triple negative disease.

Potent in vivo efficacy of oral gallium maltolate in treatment-resistant glioblastoma.

Background: Treatment-resistant glioblastoma (trGBM) is an aggressive brain tumor with a dismal prognosis, underscoring the need for better treatment options. Emerging data indicate that trGBM iron metabolism is an attractive therapeutic target. The novel iron mimetic, gallium maltolate (GaM), inhibits mitochondrial function via iron-dependent and -independent pathways. Methods: In vitro irradiated adult GBM U-87 MG cells were tested for cell viability and allowed to reach confluence prior to stereotactic implantation into the right striatum of male and female athymic rats. Advanced MRI at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Cox proportional hazards regression models, Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison as indicator of tumor growth rate. Results: In this study we demonstrate non-invasively, using longitudinal MRI surveillance, the potent antineoplastic effects of GaM in a novel rat xenograft model of trGBM, as evidenced by extended suppression of tumor growth (23.56 mm3/week untreated, 5.76 mm3/week treated, P < 0.001), a blunting of tumor perfusion, and a significant survival benefit (median overall survival: 30 days untreated, 56 days treated; P < 0.001). The therapeutic effect was confirmed histologically by the presence of abundant cytotoxic cellular swelling, a significant reduction in proliferation markers (P < 0.01), and vessel normalization characterized by prominent vessel pruning, loss of branching, and uniformity of vessel lumina. Xenograft tumors in the treatment group were further characterized by an absence of an invasive edge and a significant reduction in both, MIB-1% and mitotic index (P < 0.01 each). Transferrin receptor and ferroportin expression in GaM-treated tumors illustrated cellular iron deprivation. Additionally, treatment with GaM decreased the expression of pro-angiogenic markers (von Willebrand Factor and VEGF) and increased the expression of anti-angiogenic markers, such as Angiopoietin-2. Conclusion: Monotherapy with the iron-mimetic GaM profoundly inhibits trGBM growth and significantly extends disease-specific survival in vivo.

Frequent Upregulation Of HER2 Protein In Hormone Receptor-Positive HER2-Negative Breast Cancer After Short-Term Neoadjuvant Endocrine Therapy.

Background. Endocrine resistant metastatic disease develops in ~20-25% of hormone-receptor positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. Methods. This was a single arm, interventional phase II clinical trial evaluating 4 weeks (+/-1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥1 in IHC score following NET. Results. Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p=0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. Conclusion . Short-term NET frequently and preferentially upregulates HER2 over other HER-family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. Trial registration number: NCT03219476 Date of registration for prospectively registered trials: July 17, 2017.

Androgen receptor expression in patients with triple negative breast cancer treated with neoadjuvant chemotherapy: a single institution study.

Background: Androgen receptor (AR) expression has emerged as a potential prognostic and predictive marker in patients with triple negative breast cancer (TNBC). We conducted a retrospective analysis to evaluate pathologic complete response (pCR) rates, disease-free survival (DFS) and overall survival (OS) in patients with AR positive and AR negative TNBC treated with neoadjuvant chemotherapy. Methods: 107 patients with TNBC subtype, treated with neoadjuvant chemotherapy between June 2006 and March 2016 were evaluated for AR expression. Androgen receptors were evaluated by immunohistochemical staining (clone AR441, Dilution 1:50, Dako-Agilent, Santa Clara, CA) using whole tissue sections from archived paraffin-embedded formalin-fixed (FFPE) blocks. AR positive was defined as ≥10% nuclear stained cells. Correlation of AR expression was examined with age, BMI, race, menopausal status, tumor grade, tumor size, and lymph node involvement, and response and outcomes. Univariate and multivariate analyses were performed to determine an association with AR expression and pathologic response and survival outcomes. Results: Fifty-eight patients with available tumor specimens were stained, with twenty (34.5%) being AR-positive and thirty-eight (65.5%) being AR negative. Median age was 49 years and median follow up was 5.7 years. All patients received anthracycline based neoadjuvant chemotherapy with 13 patients (23%) receiving an additional platinum chemotherapy. BRCA mutation positivity was 7% for the entire group. No differences in age, menopausal status, BMI, race, tumor size and lymph node involvement were observed between the two groups. However, there was a statistically significant difference in tumor grade between the two groups (p=0.008). Overall pCR rate was 28% with no difference between the two groups (30% vs 26%, p=0.56). There was no statistically significant difference in median DFS (5.9 years vs 5.2 years (p=0.94) and median OS (6.2 years vs 5.4 years, p=0.98) between the AR positive and AR negative groups. Conclusions: Our study did not find an association of AR status and the pathologic responses or survival outcomes in patients with TNBC treated with neoadjuvant chemotherapy. Further studies exploring the prognostic and predictive role of AR in patients with TNBC are warranted.

Basal Ganglia Iron Content Increases with Glioma Severity Using Quantitative Susceptibility Mapping: A Potential Biomarker of Tumor Severity.

BACKGROUND AND PURPOSE: Gliomas have been found to alter iron metabolism and transport in ways that result in an expansion of their intracellular iron compartments to support aggressive tumor growth. This study used deep neural network trained quantitative susceptibility mapping to assess basal ganglia iron concentrations in glioma patients. MATERIALS AND METHODS: Ninety-two patients with brain lesions were initially enrolled in this study and fifty-nine met the inclusion criteria. Susceptibility-weighted images were collected at 3.0 T and used to construct quantitative susceptibility maps via a deep neural network-based method. The regions of interest were manually drawn within basal ganglia structures and the mean voxel intensities were extracted and averaged across multiple slices. One-way ANCOVA tests were conducted to compare the susceptibility values of groups of patients based on tumor grade while controlling for age, sex, and tumor type. RESULTS: The mean basal ganglia susceptibility for patients with grade IV tumors was higher than that for patients with grade II tumors (p = 0.00153) and was also higher for patients with grade III tumors compared to patients with grade II tumors (p = 0.020), after controlling for age, sex, and tumor type. Patient age influenced susceptibility values (p = 0.00356), while sex (p = 0.69) and tumor type (p = 0.11) did not. CONCLUSIONS: The basal ganglia iron content increased with glioma severity. Basal ganglia iron levels may thus be a useful biomarker in glioma prognosis and treatment, especially with regard to iron-based cancer therapies.

Circulating miRNAs as early indicators of diet and physical activity response in women with metastatic breast cancer.

Treatments for metastatic breast cancer (MBC) improve survival but often impose prolonged symptom burden. We performed molecular characterization of 84 miRNAs in the circulating serum of women with MBC to explore possible early indicators of intervention response. Expression levels of miR-10a-5p and miR-211-5p were downregulated in nonresponders, but upregulated in responders (miR-10a-5p: 0.40-fold and eightfold; miR 211-5p: 0.47-fold and fourfold). miR-205-5p expression was upregulated in both nonresponders and responders, but to a greater extent in responders (1.8-fold and sixfold). Additionally, levels of miR-10a-5p were negatively correlated with expression levels of IL-6 (r = -0.412). Exploration of these pathways may reveal mechanisms of action in lifestyle interventions aimed at improving quality of life and impacting disease progression for women with MBC.

Leveraging Antiprogestins in the Treatment of Metastatic Breast Cancer.

Although incurable, the prognosis for patients with metastatic breast cancer (MBC) has considerably improved with the approvals of multiple targeted and cytotoxic therapies. For hormone receptor-positive (HR+), ie, estrogen receptor and progesterone receptor positive (ER+/PgR+) and human epidermal growth factor receptor-2 negative (ie, ERBB2 gene nonamplified or HER2-) MBC, current approved treatment options include palliative endocrine therapy (ET), cyclin-dependent kinase (CDK 4/6) inhibitors, mTOR inhibitors, and PI3 kinase inhibitors. Most treatments target ER+ disease regardless of PgR status. Although the presence of PgR is crucial for ER+ cell proliferation in both normal and malignant mammary tissue, currently, there are no approved treatments that specifically target PgR. Recent literature has demonstrated the potential of antiprogestins in the treatment of MBC both in preclinical and clinical studies. Antiprogestins, including selective PgR modulators (SPRMs) that act as PgR antagonists, are a promising class of therapeutics for overcoming endocrine resistance in patients who develop activating estrogen receptor 1 (ESR1) and phosphatidylinositol 3-kinase (PI3K) gene mutations after prior endocrine therapy. Herein, we summarize the role of PgR and antiprogestins in the treatment of MBC. Other aspects on the use of functional imaging, clinical trials incorporating novel antiprogestins, and potential treatment combinations to overcome endocrine resistance will be briefly discussed.

The cytotoxicity of gallium maltolate in glioblastoma cells is enhanced by metformin through combined action on mitochondrial complex 1.

New drugs are needed for glioblastoma, an aggressive brain tumor with a dismal prognosis. We recently reported that gallium maltolate (GaM) retards the growth of glioblastoma in a rat orthotopic brain tumor model by inhibiting mitochondrial function and iron-dependent ribonucleotide reductase (RR). However, GaM's mechanism of action at the mitochondrial level is not known. Given the interaction between gallium and iron metabolism, we hypothesized that gallium might target iron-sulfur (Fe-S) cluster-containing mitochondrial proteins. Using Extracellular Flux Analyzer technology, we confirmed that after a 24-h incubation, GaM 50 µmol/L inhibited glioblastoma cell growth by <10% but inhibited cellular oxygen consumption rate by 44% and abrogated mitochondrial reserve capacity. GaM blocked mitochondrial complex I activity and produced a 2.9-fold increase in cellular ROS. NMR spectroscopy revealed that gallium binds to IscU, the bacterial scaffold protein for Fe-S cluster assembly and stabilizes its folded state. Gallium inhibited the rate of in vitro cluster assembly catalyzed by bacterial cysteine desulfurase in a reaction mixture containing IscU, Fe (II), DTT, and L-cysteine. Metformin, a complex I inhibitor, enhanced GaM's inhibition of complex I, further increased cellular ROS levels, and synergistically enhanced GaM's cytotoxicity in glioblastoma cells in 2-D and 3-D cultures. Metformin did not affect GaM action on cellular iron uptake or transferrin receptor1 expression nor did it enhance the cytotoxicity of the RR inhibitor Didox. Our results show that GaM inhibits complex I by disrupting iron-sulfur cluster assembly and that its cytotoxicity can be synergistically enhanced by metformin through combined action on complex I.

High-dose intravenous methotrexate in the management of breast cancer with leptomeningeal disease: Case series and review of the literature.

Leptomeningeal metastasis (LM) in breast cancer is associated with significant morbidity and mortality. While there is currently no standard therapy, treatment options include craniospinal radiotherapy, intrathecal chemotherapy and systemic chemotherapy. Craniospinal radiotherapy has not demonstrated improved survival and intrathecal chemotherapy is often poorly tolerated due to associated neurotoxicity. The use of systemic chemotherapy can be limited by inadequate central nervous system penetration. High-dose systemic methotrexate administered intravenously (HD-MTX), has been reported to improve quality of life and provide durable remissions for LM in breast cancer. We present three cases of metastatic breast cancer and LM with prolonged survival after administration of HD-MTX. Based on our observations and review of the literature, HD-MTX seems to be a viable treatment option for patients with LM in breast cancer, and in select cases, the use of HD-MTX, as part of a multimodality treatment plan, may be associated with prolonged survival.