Showing papers by "Naoto T. Ueno published in 2021"
TL;DR: In this article, a dual-drug ADC was proposed for treating refractory breast cancer and perhaps other cancers, and the results showed that the combination of two different payloads can achieve significant improvements in terms of treatment effect and survival.
Abstract: Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal inflammatory response, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in xenograft mouse models representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.
54 citations
TL;DR: In this article, a review of the association of body composition with breast cancer risk and treatment, including physiological mechanisms and strategies for overcoming unfavorable body composition changes that relate to breast cancer progression, is presented.
Abstract: The purpose of this review is to clarify the association of body composition with breast cancer risk and treatment, including physiological mechanisms, and to elucidate strategies for overcoming unfavorable body composition changes that relate to breast cancer progression. We have summarized updated knowledge regarding the mechanism of the negative association of altered body composition with breast cancer risk and treatment. We also review strategies for reversing unfavorable body composition based on the latest clinical trial results. Body composition changes in patients with breast cancer typically occur during menopause or as a result of chemotherapy or endocrine therapy. Dysfunction of visceral adipose tissue (VAT) in the setting of obesity underlies insulin resistance and chronic inflammation, which can lead to breast cancer development and progression. Insulin resistance and chronic inflammation are also observed in patients with breast cancer who have sarcopenia or sarcopenic obesity. Nutritional support and a personalized exercise program are the fundamental interventions for reversing unfavorable body composition. Other interventions that have been explored in specific situations include metformin, testosterone, emerging agents that directly target the adipocyte microenvironment, and bariatric surgery. A better understanding of the biology of body composition phenotypes is key to determining the best intervention program for patients with breast cancer.
31 citations
TL;DR: In this article, the authors investigated the effect of increasing tumor-infiltrating lymphocytes (TILs) on pathologic complete response (pCR) in patients with triple-negative breast cancer.
Abstract: Purpose: Increasing tumor-infiltrating lymphocytes (TILs) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. Experimental Design: We obtained pre-treatment core needle biopsies from 105 patients with stage I-III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from 10/22/2015 through 7/24/2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, PD-L1 immunohistochemistry, multiplex immunofluorescence and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathological response to NAT. Results: The pCR rate was 40% (42/105). Higher TCR clonality (median=0.2 vs 0.1, p=0.03), PD-L1 positivity (odds ratio: 2.91, p=0.020), higher CD3+:CD68+ ratio (median=14.70 vs 8.20, p=0.0128), and closer spatial proximity of T-cells to tumor cells (median=19.26µm vs 21.94µm, p=0.0169) were associated with pCR. In a multivariable model, the closer spatial proximity of T-cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage. Conclusions: In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.
25 citations
15 Jan 2021
TL;DR: Hu et al. as mentioned in this paper showed that decorin, a small leucine-rich extracellular matrix proteoglycan, is downregulated in tumors from patients with inflammatory breast cancer.
Abstract: Inflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize. The molecular mechanisms underlying the aggressiveness and metastatic propensity of IBC are largely unknown. Herein, we report that decorin (DCN), a small leucine-rich extracellular matrix proteoglycan, is downregulated in tumors from patients with IBC. Overexpression of DCN in IBC cells markedly decreased migration, invasion, and cancer stem cells in vitro and inhibited tumor growth and metastasis in IBC xenograft mouse models. Mechanistically, DCN functioned as a suppressor of invasion and tumor growth in IBC by destabilizing E-cadherin and inhibiting EGFR/ERK signaling. DCN physically binds E-cadherin in IBC cells and accelerates its degradation through an autophagy-linked lysosomal pathway. We established that DCN inhibits tumorigenesis and metastasis in IBC cells by negatively regulating the E-cadherin/EGFR/ERK axis. Our findings offer a potential therapeutic strategy for IBC, and provide a novel mechanism for IBC pathobiology. Xiaoding Hu et al. find that expression of the proteoglycan decorin is decreased in patients with inflammatory breast cancer compared to normal breast tissue and some other types of breast cancer. They demonstrate that decorin acts as a tumor suppressor in cancer cells and human xenograft mouse models by destabilizing the E-cadherin-EGFR signaling axis, and their findings suggest potential therapeutic strategies for this aggressive breast cancer.
19 citations
TL;DR: In this article, a 27-gene IO signature was used to predict the pCR of TNBC to preoperative immunochemotherapy using RNA sequencing data from 55 patients with TNBC, who received neoadjuvant immunochemicalotherapy with the PD-L1 blocker durvalumab.
Abstract: A precise predictive biomarker for TNBC response to immunochemotherapy is urgently needed. We previously established a 27-gene IO signature for TNBC derived from a previously established 101-gene model for classifying TNBC. Here we report a pilot study to assess the performance of a 27-gene IO signature in predicting the pCR of TNBC to preoperative immunochemotherapy. We obtained RNA sequencing data from the primary tumors of 55 patients with TNBC, who received neoadjuvant immunochemotherapy with the PD-L1 blocker durvalumab. We determined the power and accuracy in predicting pCR for the immunomodulatory (IM) subtype identified by the 101-gene model, the 27-gene IO signature, and PD-L1 expression by immunohistochemistry (IHC). The pCR rate was 45% (25/55). The odds ratios for pCR were as follows: IM subtype by 101-gene model, 3.14 (p = 0.054); 27-gene IO signature, 4.13 (p = 0.012); PD-L1 expression by IHC, 2.63 (p = 0.106); 27-gene IO signature in combination with PD-L1 expression by IHC, 6.53 (p = 0.003). The 27-gene IO signature has the potential to predict the pCR of primary TNBC to neoadjuvant immunochemotherapy. Further analysis in a large cohort is needed.
18 citations
TL;DR: In this paper, anti-PD1/PDL1 immune checkpoint inhibitors (ICIs) showed promising results in breast cancer, and exploration of additional actionable immune checkpoints is ongoing.
Abstract: Background. Anti-PD1/PDL1 immune checkpoint inhibitors (ICIs) showed promising results in breast cancer, and exploration of additional actionable immune checkpoints is ongoing. Inflammatory breast ...
16 citations
TL;DR: In this article, the authors provide an overview of the development of systemic treatment of inflammatory breast cancer from the past to the present by focusing on IBC clinical trials, including chemotherapy and targeted therapies.
14 citations
TL;DR: In this paper, a biindole-based mimetic mimetic of second mitochondria-derived activator of caspases (SMACs) was used to enhance the antitumor efficacy of gemcitabine in triple negative breast cancer.
Abstract: Triple-negative breast cancer (TNBC) is the most aggressive subgroup of breast cancer, and patients with TNBC have few therapeutic options. Apoptosis resistance is a hallmark of human cancer, and apoptosis regulators have been targeted for drug development for cancer treatment. One class of apoptosis regulators is the inhibitors of apoptosis proteins (IAPs). Dysregulated IAP expression has been reported in many cancers, including breast cancer, and has been shown to be responsible for resistance to chemotherapy. Therefore, IAPs have become attractive molecular targets for cancer treatment. Here, we first investigated the antitumor efficacy of birinapant (TL32711), a biindole-based bivalent mimetic of second mitochondria-derived activator of caspases (SMACs), in TNBC. We found that birinapant as a single agent has differential antiproliferation effects in TNBC cells. We next assessed whether birinapant has a synergistic effect with commonly used anticancer drugs, including entinostat (class I histone deacetylase inhibitor), cisplatin, paclitaxel, voxtalisib (PI3K inhibitor), dasatinib (Src inhibitor), erlotinib (EGFR inhibitor), and gemcitabine, in TNBC. Among these tested drugs, gemcitabine showed a strong synergistic effect with birinapant. Birinapant significantly enhanced the antitumor activity of gemcitabine in TNBC both in vitro and in xenograft mouse models through activation of the intrinsic apoptosis pathway via degradation of cIAP2 and XIAP, leading to apoptotic cell death. Our findings demonstrate the therapeutic potential of birinapant to enhance the antitumor efficacy of gemcitabine in TNBC by targeting the IAP family of proteins.
11 citations
TL;DR: In this paper, the effect of JNK-IN-8, a pan-JNK inhibitor, on TNBC tumor growth, lung metastasis, and the TME was measured in TNBC syngeneic mouse models.
Abstract: BACKGROUND Although an immunosuppressive tumor microenvironment (TME) is key for tumor progression, the molecular characteristics associated with the immunosuppressive TME remain unknown in triple-negative breast cancer (TNBC). Our previous functional proteomic study of TNBC tumors identified that C-JUN N-terminal kinase (JNK) pathway-related molecules were enriched in a cluster associated with the inflammatory pathway. However, the role of the JNK pathway in the TNBC TME is still unclear. METHODS Transcriptomic analysis was conducted using The Cancer Genome Atlas (TCGA) datasets. The effect of JNK-IN-8, a covalent pan-JNK inhibitor, on TNBC tumor growth, lung metastasis, and the TME was measured in TNBC syngeneic mouse models (n = 13 per group). Tumor (n = 43) or serum (n = 46) samples from TNBC patients were analyzed using multiplex immunohistochemistry or Luminex assay. All statistical tests were 2-sided. RESULTS CIBERSORT analysis revealed that TNBC patients with high pJNK level (n = 47) had more regulatory T cell (Treg) infiltration than those with low pJNK level (n = 47) (P = .02). Inhibition of JNK signaling statistically significantly reduced tumor growth (P < .001) and tumor-infiltrating Tregs (P = .02) while increasing the infiltration of CD8+ T cells in TNBC mouse models through the reduction of C-C motif ligand 2 (CCL2). Tumor-associated macrophages (TAMs) were the predominant cells secreting CCL2, and inhibition of JNK signaling reduced CCL2 secretion of human primary macrophages. Moreover, in patients with TNBC (n = 43), those with high levels of CCL2+ TAMs had more Treg and less CD8+ T cell infiltration (P = .04), and serum CCL2 level was associated with poor overall survival (hazard ratio = 2.65, 95% confidence interval = 1.29 to 5.44; P = .008) in TNBC patients (n = 46). CONCLUSIONS The JNK/C-JUN/CCL2 axis contributes to TNBC aggressiveness via forming an immunosuppressive TME and can offer novel therapeutic strategies for TNBC.
10 citations
TL;DR: Findings showed that OS at 5 and 10 years after diagnosis in patients with dnMBC improved over time, suggesting the contribution of HER2-targeted therapy to survival.
Abstract: The purpose of this study was to determine the change in overall survival (OS) for patients with de novo metastatic breast cancer (dnMBC) over time. We conducted a retrospective cohort study with 1981 patients with dnMBC diagnosed between January 1995 and December 2017 at The University of Texas MD Anderson Cancer Center. OS was measured from the date of diagnosis of dnMBC. OS was compared between patients diagnosed during different time periods: 5-year periods and periods defined according to when key agents were approved for clinical use. The median OS was 3.4 years. The 5- and 10-year OS rates improved over time across both types of time periods. A subgroup analysis showed that OS improved significantly over time for the estrogen-receptor-positive/HER2-positive (ER+/HER2+) subtype and exhibited a tendency toward improvement over time for the ER-negative (ER−)/HER2+ subtype. In addition, median OS was significantly longer in patients with non-inflammatory breast cancer (p = 0.02) and patients with ER+ disease, progesterone-receptor-positive disease, HER2+ disease, lower nuclear grade, locoregional therapy, and metastasis to a single organ (all p < 0.0001). These findings showed that OS at 5 and 10 years after diagnosis in patients with dnMBC improved over time. The significant improvements in OS over time for the ER+/HER2+ subtype and the tendency toward improvement for the ER−/HER2+ subtype suggest the contribution of HER2-targeted therapy to survival.
10 citations
TL;DR: The role of modified radical mastectomy (MRM) in patients with de novo stage IV inflammatory breast cancer (IBC) remains controversial. as discussed by the authors evaluated the impact of MRM on outcomes in this population.
Abstract: The role of modified radical mastectomy (MRM) in patients with de novo stage IV inflammatory breast cancer (IBC) remains controversial. We evaluated the impact of MRM on outcomes in this population. Ninety-seven women presenting with stage IV IBC were identified in an institutional database (2007–2016) and were stratified by receipt of MRM or no surgery (non-MRM). Demographic, clinicopathologic, and treatment factors were compared. Local–regional recurrence patterns were described and survival analyses were conducted. All patients initially received chemotherapy. Fifty-two patients (53.6%) underwent MRM; 47 received post-mastectomy radiation. Differences between the non-MRM and MRM groups included tumor receptor subtypes (hormone receptor-positive [HR+]/human epidermal growth factor receptor 2-positive [HER2+]: 4.4% vs. 19.2%; HR+/HER2-negative [HER2−]: 31.1% vs. 44.2%; HR-negative [HR−]/HER2+: 24.4% vs. 15.4%; and HR−/HER2−: 40.0% vs. 21.2%; p = 0.03), number of metastatic sites (3 vs. 2; p = 0.01), and clinical partial/complete response to chemotherapy (13.3% vs. 75.0%; p < 0.001). Of the 47 patients who completed trimodality therapy, 6 (12.8%) had a local–regional recurrence. Median overall survival (OS) was 19 months in the non-MRM group and 58 months in the MRM group (p < 0.001). On multivariable analysis, clinical N3 disease (hazard ratio 2.16, 95% confidence interval [CI] 1.07–4.37; p = 0.03) as well as tumor subtypes HR+/HER2− (hazard ratio 4.98, 95% CI 1.15–21.47; p = 0.03) and HR−/HER2− (hazard ratio 7.18, 95% CI 1.66–31.07; p = 0.008) were associated with decreased OS. Partial/complete response of distant disease to chemotherapy (hazard ratio 0.43, 95% CI 0.24–0.77; p = 0.005) and receipt of MRM (hazard ratio 0.52, 95% CI 0.29–0.93; p = 0.03) were independently associated with improved OS. In our retrospective study, MRM in de novo stage IV IBC patients is an independent factor associated with improved OS. Our findings strongly support the need for prospective randomized trials evaluating possible survival benefits of MRM in de novo stage IV IBC patients.
TL;DR: None of the patients was able to complete the planned 10 cycles due to the disease progression, and future studies could examine whether combining intratumoral T-VEC with concurrent systemic therapy produces better outcomes.
Abstract: Talimogene laherparepvec (T-VEC) is an immunotherapy that generates local tumor lysis and systemic antitumor immune response. We studied the efficacy of intratumoral administration of T-VEC as monotherapy for inoperable locoregional recurrence of breast cancer. T-VEC was injected intratumorally at 106 PFU/mL on day 1 (cycle 1), 108 PFU/mL on day 22 (cycle 2), and 108 PFU/mL every 2 weeks thereafter (cycles ≥ 3). Nine patients were enrolled, 6 with only locoregional disease and 3 with both locoregional and distant disease. No patient completed the planned 10 cycles or achieved complete or partial response. The median number of cycles administered was 4 (range, 3-8). Seven patients withdrew prematurely because of uncontrolled disease progression, 1 withdrew after cycle 3 because of fatigue, and 1 withdrew after cycle 4 for reasons unrelated to study treatment. Median progression-free survival and overall survival were 77 days (95% CI, 63-NA) and 361 days (95% CI, 240-NA). Two patients received 8 cycles with clinically stable disease as the best response. The most common grade 2 or higher adverse event was injection site reaction (n = 7, 78%). Future studies could examine whether combining intratumoral T-VEC with concurrent systemic therapy produces better outcomes.
TL;DR: In this paper, the authors identified PI3K/AKT/mTOR and MAPK as two potential inhibitory synergistic canonical pathways for HER2+ breast cancer and TNBC.
Abstract: Human epidermal growth factor receptor (EGFR) 2 (HER2) is overexpressed/amplified in about 25% of all breast cancers, and EGFR is overexpressed in up to 76% and amplified in up to 24% of triple-negative breast cancers (TNBC). Here, we aimed to identify inhibitors that may enhance the anti-tumor activity of neratinib for HER2+ breast cancer and TNBC. By conducting a non-biased high-throughput RNA interference screening, we identified PI3K/AKT/mTOR and MAPK as two potential inhibitory synergistic canonical pathways. We confirmed that everolimus (mTOR inhibitor) and trametinib (MEK inhibitor) enhances combinatorial anti-proliferative effects with neratinib under anchorage-independent growth conditions (p < 0.05). Compared to single agent neratinib, the combination therapies significantly enhanced tumor growth inhibition in both SUM190 HER2+ breast cancer (neratinib plus everolimus, 77%; neratinib plus trametinib, 77%; p < 0.0001) and SUM149 TNBC (neratinib plus everolimus, 71%; neratinib plus trametinib, 81%; p < 0.0001) xenograft models. Compared to single-agent neratinib, everolimus, or trametinib, both everolimus plus neratinib and trametinib plus neratinib significantly suppressed proliferation marker Ki67 and enhanced antitumor efficacy by activating the apoptosis pathway shown by increased Bim and cleaved-PARP expression. Taken together, our data justify new neratinib-based combinations for both HER2+ breast cancer and TNBC.
TL;DR: In this paper, the authors reported controlled production and evaluation of bispecific ADCs chemically functionalized with tumor-targeting small molecules, which can simultaneously target two different cancer antigens (i.e., folate receptor (FR)/human epidermal growth factor receptor 2 (HER2).
TL;DR: In this article, the role of the second ER subtype, ERβ, and its correlation with reduced metastasis was explored, and the ability of the receptor to inhibit dissemination of IBC cells and prevent metastasis.
Abstract: Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor α (ER)α-negativity. Here we explored the role of the second ER subtype, ERβ, and report expression in IBC tumors and its correlation with reduced metastasis. Ablation of ERβ in IBC cells promoted cell migration and activated gene networks that control actin reorganization, including G-protein coupled receptors and downstream effectors that activate Rho GTPases. Analysis of preclinical mouse models of IBC revealed decreased metastasis of IBC tumors when ERβ was expressed or activated by chemical agonists. Our findings support a tumor-suppressive role of ERβ by demonstrating the ability of the receptor to inhibit dissemination of IBC cells and prevent metastasis. Based on these findings, we propose ERβ as a potentially novel biomarker and therapeutic target that can inhibit IBC metastasis and reduce its associated mortality.
TL;DR: The purpose of this review is to provide a practical guide for oncologists to understand the priorities for supportive care for patients with MBC in the two phases, and to present palliative or supportive care checklists according to the disease progression phase.
TL;DR: In this paper, the frequency and clinical outcomes of contralateral axillary metastasis (CAM) in inflammatory breast cancer (IBC) patients were calculated in unilateral IBC patients at a single center.
Abstract: Nearly one-third of patients with inflammatory breast cancer (IBC) present with de novo stage IV disease. There are limited data on frequency and clinical outcomes of contralateral axillary metastasis (CAM) in IBC with no consensus diagnostic and treatment guidelines. Frequency of synchronous CAM was calculated in unilateral IBC patients at a single center (10/2004–6/2019). Clinicopathologic variables, diagnostic evaluation, treatment received, and overall survival (OS) were assessed and compared. Of 588 unilateral IBC patients, 49 (8.3%) had synchronous CAM. Of these, 32 (65.3%) also presented with metastatic disease at another distant site. CAM was not associated with age, tumor laterality, breast cancer subtype, grade, or cN stage (p > 0.05). The sensitivity/specificity to detect CAM was as follows: mammography (18.2%/99.2%), ultrasound (92.3%/95.5%), PET (90.1/99.1%), and MRI (76.0%/98.6%). Following systemic therapy, 22 patients had contralateral axillary surgery, and 18 received adjuvant contralateral nodal radiation. On multivariable analysis including tumor receptor subtypes, patients with stage IV-isolated CAM has statistically similar survival to stage III patients (HR 1.37, 95% CI 0.70–2.69, p = 0.36). Patients with Stage IV non-CAM (HR 2.18, 95% CI 1.66–2.85, p < 0.001) and stage IV-CAM plus other distant metastasis (HR 2.57, 95% CI 1.59–4.16, p < 0.001) had higher risk of death (reference: stage III disease). CAM in IBC was diagnosed in 8.3% of patients at presentation and was best identified by ultrasound and PET. We recommend routine contralateral axillary ultrasound as part of staging for all IBC patients. Diagnosis of CAM is a key first step toward much-needed prospective clinical trials evaluating management and outcomes of CAM in IBC.
TL;DR: In this paper, the authors performed whole-genome sequencing (WGS) of 20 inflammatory breast cancer (IBC) cases and paired normal blood DNA to identify genomic alterations.
Abstract: Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases. We performed WGS of 20 IBC samples and paired normal blood DNA to identify genomic alterations. For comparison, we used 23 matched non-IBC samples from the Cancer Genome Atlas Program (TCGA). We also validated our findings using WGS data from the International Cancer Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We examined a wide selection of genomic features to search for differences between IBC and conventional breast cancer. These include (i) somatic and germline single-nucleotide variants (SNVs), in both coding and non-coding regions; (ii) the mutational signature and the clonal architecture derived from these SNVs; (iii) copy number and structural variants (CNVs and SVs); and (iv) non-human sequence in the tumors (i.e., exogenous sequences of bacterial origin). Overall, IBC has similar genomic characteristics to non-IBC, including specific alterations, overall mutational load and signature, and tumor heterogeneity. In particular, we observed similar mutation frequencies between IBC and non-IBC, for each gene and most cancer-related pathways. Moreover, we found no exogenous sequences of infectious agents specific to IBC samples. Even though we could not find any strongly statistically distinguishing genomic features between the two groups, we did find some suggestive differences in IBC: (i) The MAST2 gene was more frequently mutated (20% IBC vs. 0% non-IBC). (ii) The TGF β pathway was more frequently disrupted by germline SNVs (50% vs. 13%). (iii) Different copy number profiles were observed in several genomic regions harboring cancer genes. (iv) Complex SVs were more frequent. (v) The clonal architecture was simpler, suggesting more homogenous tumor-evolutionary lineages. Whole-genome sequencing of IBC manifests a similar genomic architecture to non-IBC. We found no unique genomic alterations shared in just IBCs; however, subtle genomic differences were observed including germline alterations in TGFβ pathway genes and somatic mutations in the MAST2 kinase that could represent potential therapeutic targets.
TL;DR: In this paper, a subset of patients with intermediate 21-gene signature assay recurrence score may benefit from adjuvant chemoendocrine therapy, but a predictive strategy is needed to identify such patients.
Abstract: A subset of patients with intermediate 21-gene signature assay recurrence score may benefit from adjuvant chemoendocrine therapy, but a predictive strategy is needed to identify such patients. The 95-gene signature assay was tested to stratify patients with intermediate RS into high (95GC-H) and low (95GC-L) groups that were associated with invasive recurrence risk. Patients with ER-positive, HER2-negative, node-negative breast cancer and RS 11–25 who underwent definitive surgery and adjuvant endocrine therapy without any cytotoxic agents were included. RNA was extracted from archived formalin-fixed, paraffin-embedded samples, and 95-gene signature was calculated. 206 patients had RS of 11–25 (95GC-L, N = 163; 95GC-H, N = 43). In Cox proportional hazards model, 95GC-H was significantly associated with shorter time to recurrence than was 95GC-L (HR 5.94; 95%CI 1.81–19.53; P = 0.005). The correlation between 95-gene signature and 21-gene signature assay scores was not strong (correlation coefficient r = 0.27), which might suggest that 95-gene signature reflects biological characteristics differing from what 21-gene signature shows. The 95-gene signature stratifies patients with ER-positive, HER2-negative, node-negative invasive breast cancer and intermediate RS of 11–25 into high and low groups that are associated with recurrence risk of invasive disease. Further retrospective analysis in the prospectively accrued TAILORx population is warranted to confirm that 95-gene signature can identify patients who would benefit from adjuvant chemoendocrine therapy.
TL;DR: In this paper, the impact of body composition on pathologic complete response and survival outcomes was investigated in patients with stage III breast cancer who underwent neoadjuvant chemotherapy between January 2007 and June 2015.
Abstract: Our previous study indicated that a high amount of visceral adipose tissue was associated with poor survival outcomes in patients with early breast cancer who received neoadjuvant chemotherapy However, inconsistency was observed in the prognostic role of body composition in breast cancer treatment outcomes In the present study, we aimed to validate our previous research by performing a comprehensive body composition analysis in patients with a standardized clinical background We included 198 patients with stage III breast cancer who underwent neoadjuvant chemotherapy between January 2007 and June 2015 The impact of body composition on pathologic complete response and survival outcomes was determined Body composition measurements had no significant effect on pathologic complete response Survival analysis showed a low ratio of total visceral adipose tissue to subcutaneous adipose tissue (V/S ratio ≤ 34) was associated with shorter overall survival A changepoint method determined that a V/S ratio cutoff of 34 maximized the difference in overall survival Our study indicated the prognostic effect of body composition measurements in patients with locally advanced breast cancer compared to those with early breast cancer Further investigation will be needed to clarify the biological mechanism underlying the association of V/S ratio with prognosis in locally advanced breast cancer
TL;DR: In this paper, age-related differences in tumor biology, treatment, and clinical outcomes have been described in non-IBC patients compared with IBC patients, and the results do not support agerelated treatment de-escalation in IBC.
Abstract: Background Inflammatory breast cancer (IBC) is a rare breast malignancy with poor outcomes compared with non-IBC. Age-related differences in tumor biology, treatment, and clinical outcomes have been described in non-IBC. This study evaluated age-related differences in IBC. Methods From an institutional prospective database, patients with an IBC diagnosed from 2010 to 2019 were identified. Age was categorized as 40 years or younger, 41 to 64 years, and 65 years or older. Demographics, clinicopathologic features, and treatment received were compared. Recurrence and survival outcomes were analyzed using the log-rank test and the Cox proportional hazards model. Results Of 523 IBC patients, 113 (21.6%) were age 40 years or younger, and 72 (13.8%) were age 65 years or older. The groups did not differ statistically by race/ethnicity, N stage, clinical stage, or tumor subtype. The younger patients included a higher proportion of Hispanic and Asian patients, triple-negative breast cancer (TNBC), and clinical N2/N3. Trimodality therapy was received by 92% of the stage 3 patients, with no difference in pathologic complete response (pCR) by age (23.3% vs 28.6%; p = 0.46). During a median follow-up period of 40 months, 17% of the patients experienced locoregional recurrence and 42.8% had distant metastasis. No difference in 3-year recurrence-free survival (57.9% vs 42.6% vs 54%; p = 0.42, log rank) or overall survival (OS) (75.6% vs 77.1% vs 64.4%; p = 0.31, log rank) by age was observed, and no difference in OS by age in de novo stage 4 disease was observed. In the multivariate analysis, worse OS was associated with TNBC (hazard ratio [HR], 1.99, 95% confidence interval [CI], 1.31-3.05) and no pCR (HR, 4.45; 95% CI, 2.16-9.18). Conclusion No significant differences were observed in demographics, treatment patterns, or clinical outcomes for IBC patients age 40 years or younger compared with those age 65 years or older treated by a specialized multidisciplinary team. These findings do not support age-related treatment de-escalation in IBC.
TL;DR: In this paper, the authors examined the association of a "classic" triad of clinical signs, swollen involved breast, nipple change, and diffuse skin change, with overall survival (OS).
Abstract: BACKGROUND Inflammatory breast cancer (IBC) is a clinical diagnosis. Here, we examined the association of a "classic" triad of clinical signs, swollen involved breast, nipple change, and diffuse skin change, with overall survival (OS). METHOD Breast medical photographs from patients enrolled on a prospective IBC registry were scored by two independent reviewers as classic (triad above), not classic, and difficult to assign. Chi-squared test, Fisher's exact test, and Wilcoxon rank-sum test were used to assess differences between patient groups. Kaplan-Meier estimates and the log-rank test and Cox proportional hazard regression were used to assess the OS. RESULTS We analyzed 245 IBC patients with median age 54 (range 26-81), M0 versus M1 status (157 and 88 patients, respectively). The classic triad was significantly associated with smoking, post-menopausal status, and metastatic disease at presentation (p = 0.002, 0.013, and 0.035, respectively). Ten-year actuarial OS for not classic and difficult to assign were not significantly different and were grouped for further analyses. Ten-year OS was 29.7% among patients with the classic sign triad versus 57.2% for non-classic (p < 0.0001). The multivariate Cox regression model adjusting for clinical staging (p < 0.0001) and TNBC status (<0.0001) demonstrated classic presentation score significantly associated with poorer OS time (HR 2.6, 95% CI 1.7-3.9, p < 0.0001). CONCLUSIONS A triad of classic IBC signs independently predicted OS in patients diagnosed with IBC. Further work is warranted to understand the biology related to clinical signs and further extend the understanding of physical examination findings in IBC.
TL;DR: In this article, the effects of PEA15 phosphorylation status on tumor growth and metastasis were investigated in triple negative breast cancer (TNBC) patients, where stable cell lines were established overexpressing nonphosphorylatable (PEA15-AA) and phospho-mimetic (PEa15-DD) mutants.
Abstract: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks targeted therapies. Patients with TNBC have a very poor prognosis because the disease often metastasizes. New treatment approaches addressing drivers of metastasis and tumor growth are crucial to improving patient outcomes. Developing targeted gene therapy is thus a high priority for TNBC patients. PEA15 (phosphoprotein enriched in astrocytes, 15 kDa) is known to bind to ERK, preventing ERK from being translocated to the nucleus and hence blocking its activity. The biological function of PEA15 is tightly regulated by its phosphorylation at Ser104 and Ser116. However, the function and impact of phosphorylation status of PEA15 in the regulation of TNBC metastasis and in epithelial-to-mesenchymal transition (EMT) are not well understood. We established stable cell lines overexpressing nonphosphorylatable (PEA15-AA) and phospho-mimetic (PEA15-DD) mutants. To dissect specific cellular mechanisms regulated by PEA15 phosphorylation status, we performed RT-PCR immune and metastasis arrays. In vivo mouse models were used to determine the effects of PEA15 phosphorylation on tumor growth and metastasis. We found that the nonphosphorylatable mutant PEA15-AA prevented formation of mammospheres and expression of EMT markers in vitro and decreased tumor growth and lung metastasis in in vivo experiments when compared to control, PEA15-WT and phosphomimetic PEA15-DD. However, phosphomimetic mutant PEA15-DD promoted migration, mesenchymal marker expression, tumorigenesis, and lung metastasis in the mouse model. PEA15-AA-mediated inhibition of breast cancer cell migratory capacity and tumorigenesis was the partial result of decreased expression of interleukin-8 (IL-8). Further, we identified that expression of IL-8 was possibly mediated through one of the ERK downstream molecules, Ets-1. Our results show that PEA15 phosphorylation status serves as an important regulator for PEA15’s dual role as an oncogene or tumor suppressor and support the potential of PEA15-AA as a therapeutic strategy for treatment of TNBC.
28 Sep 2021
TL;DR: A PCR-based molecular barcoding NGS approach, quantitative amplicon sequencing (QASeq), for accurate absolute quantitation which is compatible with high multiplexing to include over 200 quantitation modules and exhibits higher and more consistent conversion yield than ddPCR in absolute molecule count quantitation.
Abstract:
Current gold standard for absolute quantitation of a specific DNA sequence is droplet digital PCR (ddPCR), which has been applied to gene copy number variation (CNV) detection. However, the number of quantitation modules in ddPCR has been limited by fluorescence channels, which thus limits the CNV sensitivity due to sampling error following Poisson distribution. Here we develop a PCR-based molecular barcoding NGS approach, quantitative amplicon sequencing (QASeq), for accurate absolute quantitation which is compatible with high multiplexing to include over 200 quantitation modules. By attaching barcodes to individual target molecules with high efficiency, 2-plex QASeq exhibits higher and more consistent conversion yield than ddPCR in absolute molecule count quantitation. Multiplexed QASeq improves CNV sensitivity to allow confident distinguishment of 2.05 ploidy from normal 2.00 ploidy. We applied multiplexed QASeq to serial longitudinal plasma cfDNA samples from patients with metastatic ERBB2+ (HER2+) breast cancer seeking association with tumor progression. We further show an RNA QASeq panel for targeted expression profiling on a wide range of RNA samples including tumor formalin-fixed, paraffin-embedded (FFPE) RNA.
TL;DR: In this article, the authors conducted a systematic review to determine whether neoadjuvant chemotherapy plus targeted therapy results in a higher pathologic complete response (pCR) rate than NEODUvant chemotherapy alone in patients with inflammatory breast cancer.
Abstract: Background The current use of targeted therapy plus neoadjuvant chemotherapy for inflammatory breast cancer (IBC) is based on data extrapolated from studies in non-IBC. We conducted a systematic review to determine whether neoadjuvant chemotherapy plus targeted therapy results in a higher pathologic complete response (pCR) rate than neoadjuvant chemotherapy alone in patients with IBC. Method and findings This systematic review was registered in the PROSPERO register with registration number CRD42018089465. We searched MEDLINE & PubMed, EMBASE, and EBSCO from December 1998 through July 2020. All English-language clinical studies, both randomized and non-randomized, that evaluated neoadjuvant systemic treatment with or without targeted therapy before definitive surgery and reported the pCR results of IBC patients. First reviewer extracted data and assessed the risk of bias using the Risk of Bias In Non-randomized Studies of Interventions tool. Second reviewer confirmed the accuracy. Studies were divided into 3 groups according to systemic treatment: chemotherapy with targeted therapy, chemotherapy alone, and high-dose chemotherapy with hematopoietic stem cell support (HSCS). Of 995 screened studies, 23 with 1,269 IBC patients met the inclusion criteria. For each of the 3 groups of studies, we computed a weighted average of the pCR rates across all studies with confidence interval (CI). The weighted averages (95% CIs) were as follows: chemotherapy with targeted therapy, 31.6% (26.4%-37.3%), chemotherapy alone, 13.0% (10.3%-16.2%), and high-dose chemotherapy with HSCS, 23.0% (18.7%-27.7%). The high pCR by targeted therapy group came from anti-HER2 therapy, 54.4% (44.3%-64.0%). Key limitations of this study included no randomized clinical studies that included only IBC patients. Conclusion Neoadjuvant chemotherapy plus targeted therapy is more effective than neoadjuvant chemotherapy alone for IBC patients. These findings support current IBC standard practice in particular the use of anti-HER2 targeted therapy.
TL;DR: The roles of CT, skeletal scintigraphy, SPECT/CT, MRI, PET/CT and PET/MRI will be reviewed and therapeutic response criteria specifically designed to evaluate bone metastases can guide image interpretation.
Abstract: The mechanisms by which tumors metastasize to bone are complex. Upon the successful establishment of metastatic deposits in the skeleton, detection of the disease becomes essential for therapeutic planning. The roles of CT, skeletal scintigraphy, SPECT/CT, MRI, PET/CT and PET/MRI will be reviewed. Therapeutic response criteria specifically designed to evaluate bone metastases (MD Anderson/MDA criteria) can guide image interpretation. Knowledge of therapeutic strategies such as systemic therapy with bisphosphonates or radiopharmaceuticals, radiation therapy, surgery, and percutaneous interventions such as vertebroplasty and radiofrequency ablation can help the radiologist produce reports that will provide maximum benefit to clinicians and patients.