We lack consensus guidelines for management of pleomorphic and florid LCIS (PL- and FL-LCIS), resulting in ad hoc management of patients, both within and across institutions. This review discusses ...current definitions, variants, and management controversies. LCIS with necrosis should be included in the definition of FL-LCIS, and an inflammatory infiltrate associated with LCIS or with extracellular mucin production, are higher-risk variants. If we define our treatment goal in terms of crude annual recurrence at 1% per year, in line with DCIS recurrence goals, we can standardize treatment to achieve this, and assess the outcomes over time across multiple institutions. Based on published PL-LCIS studies, guidelines should include obtaining negative margins (no-tumor-on-ink), as positive margins are more frequently seen in cases of recurrence (38.4% vs 22.8% for all cases). Testing PL-LCIS for Estrogen Receptor (ER) can be recommended to guide chemoprevention decision-making (given a 21% ER negative rate). HER2 status in both PL- and FL-LCIS (14% and 6% positive respectively) can help inform treatment decisions (e.g. favor DCIS-style management if positive), because unlike DCIS, treatment of LCIS is not uniform. Finally, a recommendation for or against radiation therapy in the setting of breast conservation, for PL-LCIS and FL-LCIS would also clearly establish its utility over time.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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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.
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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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recently, organoid technology has been used to generate a large repository of breast cancer organoids. Here we present an extensive evaluation of the ability of organoid culture technology to ...preserve complex stem/progenitor and differentiated cell types via long-term propagation of normal human mammary tissues. Basal/stem and luminal progenitor cells can differentiate in culture to generate mature basal and luminal cell types, including ER+ cells that have been challenging to maintain in culture. Cells associated with increased cancer risk can also be propagated. Single-cell analyses of matched organoid cultures and native tissues by mass cytometry for 38 markers provide a higher resolution representation of the multiple mammary epithelial cell types in the organoids, and demonstrate that protein expression patterns of the tissue of origin can be preserved in culture. These studies indicate that organoid cultures provide a valuable platform for studies of mammary differentiation, transformation, and breast cancer risk.
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.
Transitional care (TC) has received widespread attention from researchers, health system leaders, clinicians, and policy makers as they attempt to improve health outcomes and reduce preventable ...hospital readmissions, yet little is known about the critical elements of effective TC and how they relate to patients’ and caregivers’ needs and experiences. To address this gap, the Patient‐Centered Outcomes Research Institute (PCORI) funded a national study, Achieving patient‐centered Care and optimized Health In care transitions by Evaluating the Value of Evidence (Project ACHIEVE). A primary aim of the study is the identification of TC components that yield desired patient and caregiver outcomes. Project ACHIEVE established a multistakeholder workgroup to recommend essential TC components for vulnerable Medicare beneficiaries. Guided by a review of published evidence, the workgroup identified and defined a preliminary set of components and then analyzed how well the set aligned with real‐world patients' and caregivers' experiences. Through this process, the workgroup identified eight TC components: patient engagement, caregiver engagement, complexity and medication management, patient education, caregiver education, patients' and caregivers' well‐being, care continuity, and accountability. Although the degree of attention given to each component will vary based on the specific needs of patients and caregivers, workgroup members agree that health systems need to address all components to ensure optimal TC for all Medicare beneficiaries.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. ...Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62–0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85–0.92). The Fleiss' kappa value for <60 vs ≥60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant ...bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, 95% confidence interval (CI): 30,74) than in hormone receptor-positive (HR)BC 5/78 patients or 6% (95%CI: 2,14). Within the HRBCs, basal-like subtype was significantly associated with pCR (P= 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610,P= 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465,P= 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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.
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