MicroRNAs are well suited to regulate tumor metastasis because of their capacity to coordinately repress numerous target genes, thereby potentially enabling their intervention at multiple steps of ...the invasion-metastasis cascade. We identify a microRNA exemplifying these attributes, miR-31, whose expression correlates inversely with metastasis in human breast cancer patients. Overexpression of miR-31 in otherwise-aggressive breast tumor cells suppresses metastasis. We deploy a stable microRNA sponge strategy to inhibit miR-31 in vivo; this allows otherwise-nonaggressive breast cancer cells to metastasize. These phenotypes do not involve confounding influences on primary tumor development and are specifically attributable to miR-31-mediated inhibition of several steps of metastasis, including local invasion, extravasation or initial survival at a distant site, and metastatic colonization. Such pleiotropy is achieved via coordinate repression of a cohort of metastasis-promoting genes, including RhoA. Indeed, RhoA re-expression partially reverses miR-31-imposed metastasis suppression. These findings indicate that miR-31 uses multiple mechanisms to oppose metastasis.
Background
Before initiating cancer therapy, a diagnostic tumor tissue sample evaluated within a pathology laboratory by a pathologist is essential to confirm the malignancy type and provide key ...prognostic factors that direct the treatment offered.
Methods
Pathology evaluation includes multiple expensive reagents, complex equipment, and both laboratory and pathologist technical skills. By using breast cancer as an example, at a minimum, key tumor prognostic information required before the initiation of treatment includes subtype, tumor grade, tumor size, lymph node status when possible, and biomarker expression determined by immunohistochemistry for estrogen receptor. The additional determination of biomarker expression of progesterone receptor and human epidermal growth factor receptor (HER2) is the standard of care in high‐resource settings, but assays may not be affordable in low‐income and middle‐income countries.
Results
With positive tests, patients are eligible for either tamoxifen (for estrogen receptor‐positive/progesterone receptor‐positive cancers) or monoclonal antibody therapy (for HER2‐positive cancers). For settings in which endocrine therapy and/or HER2‐targeted therapy is unavailable, biomarker studies have no utility, and high‐resource setting standards for pathology evaluation and reporting are unachievable. Resource‐stratified pathology evaluation guidelines in cancer diagnosis have not been developed, in contrast to excellent comprehensive, resource‐stratified clinical guidelines for use in low‐income and middle‐income countries, and these are long overdue.
Conclusions
The challenges of pathology evaluation in the context of global health are being met by innovative solutions, which may change the face of pathology practice.
There is an urgent need for a set of resource‐stratified pathology evaluation guidelines to complement the current National Comprehensive Cancer Network resource‐stratified frameworks for diagnosis and treatment. Such guidelines are needed so that laboratories in lower resource settings can more practically meet globally acceptable standards appropriate to their resources and matched with stratified therapies available to the populations they serve.
Safety-net hospitals have higher-than-expected readmission rates. The relative roles of the mean disadvantage of neighborhoods the hospitals serve and the disadvantage of individual patients in ...predicting a patient's readmission are unclear.
To examine the independent contributions of the patient's neighborhood and the hospital's service area to risk for 30-day readmission.
Retrospective observational study.
Maryland.
All Maryland residents discharged from a Maryland hospital in 2015.
Predictors included the disadvantage of neighborhoods for each Maryland resident (area disadvantage index) and the mean disadvantage of each hospital's discharged patients (safety-net index). The primary outcome was unplanned 30-day hospital readmission. Generalized estimating equations and marginal modeling were used to estimate readmission rates. Results were adjusted for clinical readmission risk.
13.4% of discharged patients were readmitted within 30 days. Patients living in neighborhoods at the 90th percentile of disadvantage had a readmission rate of 14.1% (95% CI, 13.6% to 14.5%) compared with 12.5% (CI, 11.8% to 13.2%) for similar patients living in neighborhoods at the 10th percentile. Patients discharged from hospitals at the 90th percentile of safety-net status had a readmission rate of 14.8% (CI, 13.4% to 16.1%) compared with 11.6% (CI, 10.5% to 12.7%) for similar patients discharged from hospitals at the 10th percentile of safety-net status. The association of readmission risk with the hospital's safety-net index was approximately twice the observed association with the patient's neighborhood disadvantage status.
Generalizability outside Maryland is unknown. Confounding may be present.
In Maryland, residing in a disadvantaged neighborhood and being discharged from a hospital serving a large proportion of disadvantaged neighborhoods are independently associated with increased risk for readmission.
National Institute on Minority Health and Health Disparities and Maryland Health Services Cost Review Commission.
Background
The diagnosis of mixed invasive ductal and lobular carcinoma (IDC‐L) in clinical practice is often associated with uncertainty related to its prognosis and response to systemic therapies. ...With the increasing recognition of invasive lobular carcinoma (ILC) as a distinct disease subtype, questions surrounding IDC‐L become even more relevant. In this study, we took advantage of a detailed clinical database to compare IDC‐L and ILC regarding clinicopathologic and treatment characteristics, prognostic power of histologic grade, and survival outcomes.
Materials and Methods
In this retrospective cohort study, we identified 811 patients diagnosed with early‐stage breast cancer with IDC‐L or ILC. Descriptive statistics were performed to compare baseline clinicopathologic characteristics and treatments. Survival rates were subsequently analyzed using the Kaplan–Meier method and compared using the Cox proportional hazards model.
Results
Patients with ILC had more commonly multifocal disease, low to intermediate histologic grade, and HER2‐negative disease. Histologic grade was prognostic for patients with IDC‐L but had no significant discriminatory power in patients with ILC. Among postmenopausal women, those with IDC‐L had significantly better outcomes when compared with those with ILC: disease‐free survival (DFS) and overall survival (OS; adjusted hazard ratio HR, 0.54; 95% confidence interval CI 0.31–0.95). Finally, postmenopausal women treated with an aromatase inhibitor had more favorable DFS and OS than those treated with tamoxifen only (OS adjusted HR, 0.50; 95% CI, 0.29–0.87), which was similar for both histologic types (p = .212).
Conclusion
IDC‐L tumors have a better prognosis than ILC tumors, particularly among postmenopausal women. Histologic grade is an important prognostic factor in IDC‐L but not in ILC.
Implications for Practice
This study compared mixed invasive ductal and lobular carcinoma (IDC‐L) with invasive lobular carcinomas (ILCs) to assess the overall prognosis, the prognostic role of histologic grade, and response to systemic therapy. It was found that patients with IDC‐L tumors have a better prognosis than ILC, particularly among postmenopausal women, which may impact follow‐up strategies. Moreover, although histologic grade failed to stratify the risk of ILC, it showed an important prognostic power in IDC‐L, thus highlighting its clinical utility to guide treatment decisions of IDC‐L. Finally, the disease‐free survival advantage of adjuvant aromatase inhibitors over tamoxifen in ILC was consistent in IDC‐L.
摘要
背景。临床实践中混合浸润性导管和小叶癌 (IDC‐L) 的诊断通常与其预后和系统治疗反应相关的不确定性有关。随着人们日益认识到浸润性小叶癌 (ILC) 是一种独特的疾病亚型，围绕 IDC‐L 而产生的问题变得更加相关。在本次研究中，我们利用详细的临床数据库来比较 IDC‐L 和 ILC 的临床病理和治疗特征、组织学分级的预后能力以及生存预后。
材料和方法。在本次回顾性队列研究中，我们找到了 811 名被诊断为患有 IDC‐L 或 ILC 的早期乳腺癌患者。我们执行了描述性统计，以比较基线临床病理特征和治疗。随后，我们使用Kaplan–Meier分析方法对生存率进行了分析，并使用Cox比例风险模型进行了比较。
结果。ILC 患者患有更常见的多灶性疾病，组织学分级介于低级至中级之间，且为 HER2 阴性。组织学分级对 IDC‐L 患者而言是预后因素，但在 ILC 患者中没有显著的区分能力。在绝经后女性中，IDC‐L 患者的预后明显好于 ILC 患者:无病生存期 (DFS) 和总生存期 OS；校正风险比 (HR)，0.54；95% 置信区间 (CI) 0.31–0.95。最后，采用芳香化酶抑制剂治疗的绝经后女性在 DFS 和 OS 方面比仅采用他莫昔芬治疗的绝经后女性更好(OS 校正 HR，0.50；95% CI，0.29–0.87)，后一种治疗方式对这两种组织学类型而言效果相似 (p = 0.212)。
结论。IDC‐L 肿瘤的预后要好于 ILC 肿瘤，尤其在绝经后女性中更是如此。在 IDC‐L(而非 ILC)中，组织学分级是一个重要的预后因素。
实践意义:本研究将混合浸润性导管和小叶癌 (IDC‐L) 与浸润性小叶癌(ILC)进行对比，以评估总体预后、组织学分级的预后作用以及系统治疗的反应。研究发现，IDC‐L 肿瘤患者的预后要好于 ILC 患者，尤其在绝经后女性中更是如此，这可能会影响随访策略。此外，尽管组织学分级未能对 ILC 的风险进行分层，但是，它在 IDC‐L 中显示出重要的预后能力，因而突显其指导 IDC‐L 治疗决策的临床实用性。最后，辅助芳香化酶抑制剂在 ILC 中相对于他莫昔芬的无病生存期优势与在 IDC‐L 中的优势是一致的。
In this retrospective analysis, a large, detailed, and curated single center database was used to compare clinicopathologic features and outcomes between invasive lobular carcinoma and mixed invasive ductal and lobular carcinomas, focusing on the prognostic implications of histological grade and taking into consideration the differences in systemic therapies.
Currently, no targeted therapies are available for metastatic triplenegative breast cancer (mTNBC). We evaluated the safety, efficacy, and biomarkers of response to cabozantinib, a multikinase ...inhibitor, in patients with mTNBC. We conducted a single arm phase II and biomarker study that enrolled patients with measurable mTNBC. Patients received cabozantinib (60 mg daily) on a 3‐week cycle and were restaged after 6 weeks and then every 9 weeks. The primary endpoint was objective response rate. Predefined secondary endpoints included progression‐free survival (PFS), toxicity, and tissue and blood circulating cell and protein biomarkers. Of 35 patients who initiated protocol therapy, 3 (9% 95% confidence interval (CI): 2, 26) achieved a partial response (PR). Nine patients achieved stable disease (SD) for at least 15 weeks, and thus the clinical benefit rate (PR+SD) was 34% 95% CI: 19, 52. Median PFS was 2.0 months 95% CI: 1.3, 3.3. The most common toxicities were fatigue, diarrhea, mucositis, and palmar‐plantar erythrodysesthesia. There were no grade 4 toxicities, but 12 patients (34%) required dose reduction. Two patients had TNBCs with MET amplification. During cabozantinib therapy, there were significant and durable increases in plasma placental growth factor, vascular endothelial growth factor (VEGF), VEGF‐D, stromal cell‐derived factor 1a, and carbonic anhydrase IX, and circulating CD3 + cells and CD8 + T lymphocytes, and decreases in plasma soluble VEGF receptor 2 and CD14+ monocytes (all p < .05). Higher baseline concentrations of soluble MET (sMET) associated with longer PFS (p = .03). In conclusion, cabozantinib showed encouraging safety and efficacy signals but did not meet the primary endpoint in pretreated mTNBC. Exploratory analyses of circulating biomarkers showed that cabozantinib induces systemic changes consistent with activation of the immune system and antiangiogenic activity, and that sMET should be further evaluated a potential biomarker of response.
Implications for Practice
Triple‐negative breast cancer (TNBC)—a disease with a dearth of effective therapies—often overexpress MET, which is associated with poor clinical outcomes. However, clinical studies of agents targeting MET and VEGF pathways—alone or in combination—have shown disappointing results. This study of cabozantinib (a dual VEGFR2/MET) in metastatic TNBC, while not meeting its prespecified endpoint, showed that treatment is associated with circulating biomarker changes, and is active in a subset of patients. Furthermore, this study demonstrates that cabozantinib therapy induces a systemic increase in cytotoxic lymphocyte populations and a decrease in immunosuppressive myeloid populations. This supports the testing of combinations of cabozantinib with immunotherapy in future studies in breast cancer patients.
This study evaluates the safety, efficacy, and biomarkers of response to cabozantinib, a multikinase inhibitor, in patients with metastatic triple‐negative breast cancer (mTNBC). Cabozantinib showed encouraging safety and efficacy signals but did not meet the prespecified primary endpoint in pretreated mTNBC. Exploratory analyses of circulating biomarkers showed that cabozantinib induces systemic changes consistent with activation of the immune system and antiangiogenic activity, and soluble MET should be further evaluated as a potential biomarker of response.
Breast cancer is the leading cause of cancer mortality among women in developing countries. Timely and accurate histopathological diagnosis of breast cancer is critical to delivering high-quality ...breast cancer care to patients in low- and middle-income countries (LMIC). The most important prognostic factors in breast cancer along with tumor size and nodal status are tumor grade, estrogen receptor status, as well as HER2 status in countries where specific targeted therapies are available. In addition, detailed and complete cancer registry data are needed to assess a country's disease burden and guide disease prioritization and allocation of resources for breast cancer treatment. Innovations in leapfrog technology and low-cost point-of-care tests for molecular evaluations are needed to provide accurate and timely pathology, with the ultimate goal of improving survival outcomes for patients with breast cancer in LMIC.
Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel ...therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC.
We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR).
Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB
T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells.
In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target.
www.
gov , NCT02876302. Registered 23 August 2016.
Lymphocytic lobulitis (LL) is characterized by prominent lymphocytic infiltrates centered on lobules. Sclerosing lymphocytic lobulitis (SCLL) associated with diabetes mellitus (DM) or autoimmune ...disease (AI) was the first type to be described. Subsequently, non-sclerosing LL (NSCLL) was reported as an incidental finding in prophylactic mastectomies due to high risk germline mutations or a family history of breast cancer. The two types of LL were distinguished by stromal features and a predominant population of B-cells in the former and T-cells in the latter. In this study, 8 cases of NSCLL detected clinically or by screening were compared to 44 cases of SCLL. One case of NSCLL presented as a palpable mass, 2 as masses on screening, and 5 as MRI enhancement. In contrast, 80% of SCLL cases presented as palpable masses. Half the cases of NSCLL were associated with a BRCA1 or 2 mutation compared to 1 case of SCLL (2%). Three additional cases of NSCLL were associated with a strong family and/or personal history of breast cancer. Almost half (52%) of SCLL cases were associated with DM or AI, but only 25% of NSCLL. Immunoperoxidase studies confirmed a predominance of T-cells in NSCLL and B-cells in SCLL associated with DM or AI. It is important for pathologists to be aware of this new observation that NSCLL can be detected as a palpable mass or an imaging finding in diagnostic biopsies, as its presence can be indicative of a significant risk for breast cancer.
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Abstract
Objectives
Management of the axilla in breast cancer patients has evolved considerably since the introduction of the sentinel lymph node (SLN) biopsy in the 1990s. Several new clinical and ...technological developments in the last decade warrant special consideration due to their impact on pathology practice.
Methods
This review covers the SLN biopsy procedure, issues in the histopathologic and molecular diagnosis of the SLN, and most importantly, evidence from recent practice-changing clinical trials.
Results
ACOSOG Z0011, IBCSG 23-01, and AMAROS trials have shown that early-stage breast cancer patients who have limited metastatic involvement of the SLNs do not benefit from completion axillary dissections.
Conclusions
It is not necessary for pathologists to search for all small metastases to predict non-SLN involvement, regional recurrence, or death due to disease. Processing should be designed with the goal of detecting macrometastases. Multiple levels, routine immunohistochemistry, and molecular testing are not recommended.
Fixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE ...samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials.
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