The σ
receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using
-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1
)-yl)butyl)-2-(2-
...F-fluoroethoxy)-5-methylbenzamide (
F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of
F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether
F-ISO-1 PET could provide an in vivo measure of tumor proliferative status, and we hypothesized that uptake would correlate with a tissue-based assay of proliferation, namely Ki-67 expression.
Twenty-eight women with 29 primary invasive breast cancers were prospectively enrolled in a clinical trial (NCT02284919) between March 2015 and January 2017. Each received an injection of 278-527 MBq of
F-ISO-1 and then underwent PET/CT imaging of the breasts 50-55 min later. In vivo uptake of
F-ISO-1 was quantitated by SUV
and distribution volume ratios and was compared with ex vivo immunohistochemistry for Ki-67. Wilcoxon rank-sum tests assessed uptake differences across Ki-67 thresholds, and Spearman correlation tested associations between uptake and Ki-67.
Tumor SUV
(median, 2.0 g/mL; range, 1.3-3.3 g/mL), partial-volume-corrected SUV
, and SUV ratios were tested against Ki-67. Tumors stratified into the high-Ki-67 (≥20%) group had SUV
greater than the low-Ki-67 (<20%) group (
= 0.02). SUV
exhibited a positive correlation with Ki-67 across all breast cancer subtypes (ρ = 0.46,
= 0.01,
= 29). Partial-volume-corrected SUV
was positively correlated with Ki-67 for invasive ductal carcinoma (ρ = 0.51,
= 0.02,
= 21). Tumor-to-normal-tissue ratios and tumor distribution volume ratio did not correlate with Ki-67 (
> 0.05).
F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.
Greater than 70% of human breast cancers express the androgen receptor (AR). Emerging preclinical and clinical data suggest that AR may play a role in breast cancer pathogenesis and may serve as a ...therapeutic target in certain more difficult-to-treat breast cancer subtypes, such as triple-negative breast cancer. Although this is an area of active investigation, the clinical significance of this hormone receptor as a prognostic/predictive marker and its functional role in tumorigenesis is unclear. This review provides an update on the advances made in the last several years regarding the role of AR as a prognostic/predictive biomarker in breast cancer, the underlying biology of AR signaling in breast cancer development and the available clinical data for the use of androgen inhibition in the treatment of AR
triple-negative breast cancer.
Agents targeting programmed death ligand 1 (PD-L1) have demonstrated efficacy in triple-negative breast cancer (TNBC) when combined with chemotherapy and are now the standard of care in patients with ...PD-L1-positive metastatic disease. In contrast to microtubule-targeting agents, the effect of combining platinum compounds with programmed cell death 1 (PD-1)/PD-L1 immunotherapy has not been extensively determined.
To evaluate the efficacy of atezolizumab with carboplatin in patients with metastatic TNBC.
This phase 2 randomized clinical trial was conducted in 6 centers from August 2017 to June 2021.
Patients with metastatic TNBC were randomized to receive carboplatin area under the curve (AUC) 6 alone or with atezolizumab, 1200 mg, every 3 weeks until disease progression or unacceptable toxic effects with a 3-year duration of follow-up.
The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). Other objectives included correlation of response with tumor PD-L1 levels, tumor-infiltrating lymphocytes (TILs), tumor DNA- and RNA-sequenced biomarkers, TNBC subtyping, and multiplex analyses of immune markers.
All 106 patients with metastatic TNBC who were enrolled were female with a mean (range) age of 55 (27-79) years, of which 12 (19%) identified as African American/Black, 1 (1%) as Asian, 73 (69%) as White, and 11 (10%) as unknown. Patients were randomized and received either carboplatin (n = 50) or carboplatin and atezolizumab (n = 56). The combination improved PFS (hazard ratio HR, 0.66; 95% CI, 0.44-1.01; P = .05) from a median of 2.2 to 4.1 months, increased ORR from 8.0% (95% CI, 3.2%-18.8%) to 30.4% (95% CI, 19.9%-43.3%), increased CBR at 6 months from 18.0% (95% CI, 9.8%-30.1%) to 37.5% (95% CI, 26.0%-50.6%), and improved OS (HR, 0.60; 95% CI, 0.37-0.96; P = .03) from a median of 8.6 to 12.6 months. Subgroup analysis showed PD-L1-positive tumors did not benefit more from adding atezolizumab (HR, 0.62; 95% CI, 0.23-1.65; P = .35). Patients with high TILs (HR, 0.12; 95% CI, 0.30-0.50), high mutation burden (HR, 0.50; 95% CI, 0.23-1.06), and prior chemotherapy (HR, 0.59; 95% CI, 0.36-0.95) received greater benefit on the combination. Patients with obesity and patients with more than 125 mg/dL on-treatment blood glucose levels were associated with better PFS (HR, 0.35; 95% CI, 0.10-1.80) on the combination. TNBC subtypes benefited from adding atezolizumab, except the luminal androgen receptor subtype.
In this randomized clinical trial, the addition of atezolizumab to carboplatin significantly improved survival of patients with metastatic TNBC regardless of PD-L1 status. Further, lower risk of disease progression was associated with increased TILs, higher mutation burden, obesity, and uncontrolled blood glucose levels.
ClinicalTrials.gov Identifier: NCT03206203.
Carriers of a pathogenic/likely pathogenic (P/LP)
variant are at increased risk of pancreatic ductal adenocarcinoma (PDAC), yet current guidelines recommend surveillance only for those with a family ...history of PDAC. We aimed to investigate outcomes of endoscopic ultrasound (EUS)-based PDAC surveillance in
carriers without a family history of PDAC. We performed a retrospective analysis of all P/LP
carriers who underwent EUS at a tertiary care center. Of 194 P/LP
carriers who underwent EUS, 64 (33%) had no family history of PDAC and had at least 1 EUS for PDAC surveillance. These individuals underwent 143 total EUSs, were predominantly female (72%), and
carriers (73%), with the majority having a personal history of cancer other than PDAC (67%). The median age at time of first EUS was 62 years interquartile range (IQR), 53-67 years and a median of 2 EUSs (IQR 1-3) were performed per patient, with a median of 3 years (IQR 2-4.5 years) between the first and last EUS for those with more than 1 EUS. Pancreatic abnormalities were detected in 44%, including cysts in 27%, and incidental luminal abnormalities in 41%. Eight percent developed a new pancreatic mass or cyst during surveillance, 2 individuals developed PDAC, and no serious complications resulted from surveillance. After discussion of the risks, limitations, and potential benefits, PDAC surveillance can be considered in
carriers without a family history of PDAC; however, the effectiveness of PDAC surveillance in this population requires further study. PREVENTION RELEVANCE:
carriers have increased pancreatic ductal adenocarcinoma (PDAC) risk, yet are typically not eligible for PDAC surveillance in the absence of PDAC family history. Herein we describe outcomes of PDAC surveillance in
carriers without a family history of PDAC, showing that PDAC surveillance can be considered in this high-risk group.
Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous ...RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET.
Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated.
Mean age was 50 years (35-64); median Eastern Cooperative Oncology Group 0 (0-1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients' blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67.
Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible.
Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.
Hereditary mixed polyposis syndrome (HMPS) is a hereditary syndrome that is characterized by multiple colon polyps of mixed pathologic subtypes and an increased risk for colorectal cancer. A 40 kb ...duplication in the 5′ regulatory region of the
GREM1
gene was recently found to be the causal mutation in a subset of Ashkenazi Jewish families with HMPS. Given this discovery, the
GREM1
5′ regulatory region is now analyzed on many different multi-gene cancer panels, however the data on duplications distinct from the 40 kb duplication remains minimal. Herein we report a novel 24 kb tandem duplication of the 5′ regulatory region of
GREM1
in a patient without Ashkenazi Jewish heritage, who had a family history that was concerning for Lynch syndrome and satisfied Amsterdam II criteria. This is only the third reported
GREM1
duplication separate from the 40 kb Ashkenazi Jewish duplication, and is the only reported duplication to selectively involve exon 1 of
GREM1
. This finding supports comprehensive testing of the
GREM1
regulatory region in families of all ethnicities with multiple colon polyps or colon cancer, and when Lynch syndrome is suspected.
Aqueous root extract of Oroxylum indicum was evaluated in rats against dinitrobenzene sulfonic acid (DNBS) induced colitis.
Rats were pre-treated orally for seven days and continued for four days ...after the induction of colitis with OI(aq) (100, 200, and 400 mg/kg) or vehicle. Colitis was induced by intracolonic instillation of 25 mg of DNBS per rat dissolved in 50% alcohol and 4 days later, the colonic mucosal damage was analyzed along with food intake, body weight, colon weight, spleen weight, histological damage, myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels, reduced glutathione (GSH), and nitric oxide levels in colonic tissue homogenate.
Significant reduction in gross damage area, weight loss and increase in colonic and spleen weight were evident in test substance-pretreated animals' dose dependently as compared to vehicle treated control. These effects were confirmed biochemically by a reduction in colonic myeloperoxidase activity, malondialdehyde levels, nitric oxide levels, and increase in reduced glutathione (GSH) levels. Furthermore, microscopic examination revealed diminution of inflammatory cell infiltration and submucosal edema in colon segments of rats treated with OI(aq).
The results demonstrate the protective effect of OI(aq) in the animal model of acute colitis possibly through an antioxidant, anti-lipoperoxidative or due to reduction in nitric oxide generation.
Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most ...patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1.
This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.
Purpose of Review
Polygenic risk scores (PRS) for breast cancer (BC) estimate risk based on the cumulative impact of single-nucleotide polymorphisms. This review outlines current data regarding ...potential applications of breast cancer PRS.
Recent Findings
PRS may have use in unaffected and affected individuals and in those with and without germline pathogenic variants. Incorporation of clinical risk factors strengthens estimates. Multi-ancestry PRS have mitigated but not resolved concerns about applicability across ancestry groups.
Summary
PRS represents an important, emerging component of BC risk estimation. Research will help inform optimal utilization and communication, as well as clinical and psychological impact.
The demonstrated efficacy of pharmacologic antiestrogen therapy in treating hormone receptor-positive breast cancer has changed the landscape of treatment for the majority of women with metastatic ...disease, providing them with a well-tolerated therapeutic alternative to surgical oophorectomy and chemotherapy. A multitude of clinical trials have evaluated the various endocrine agents alone or in combination. Studies have established ovarian suppression as key for the management of premenopausal metastatic breast cancer patients, and aromatase inhibitor therapy as first-line treatment for their postmenopausal counterparts. Fulvestrant (Faslodex, AstraZeneca) has also been found to be efficacious and has been studied in the first-line and second-line settings. De novo and acquired endocrine therapy resistance represent a major challenge to the ongoing treatment of patients with hormone receptor-positive disease; strategies to circumvent or delay resistance, including the use of combination endocrine therapy and endocrine therapy with agents targeting various growth-factor signaling pathways, represent an active area of investigation. This review provides a summary of the various landmark trials that have established our current standards of practice in the management of patients with hormone receptor-positive metastatic breast cancer. A discussion of future directions and ongoing studies is also provided.
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