Rutika Mehta

Prognostic impact of ALDH1 in breast cancer: a story of stem cells and tumor microenvironment

The concept of cancer cells being hierarchically organized and arising from their own progenitor stem cells will have important implications on cancer therapy. If this hypothesis were to be true then the paucity of estrogen receptors in stem cells as well as their inherent drug resistance mechanisms pose a challenge to current targeted therapies. In this study, we sought to examine the prognostic relevance of ALDH1, a putative cancer stem cell marker, by immunohistochemistry. The four cohorts analyzed included an adjuvantly treated series of 245 invasive cancers, a neoadjuvantly treated series of 34 cases, and two series of 58 and 40 triple negative cases, respectively. Both tumor cell and stromal expression for ALDH1 was evaluated, where possible. Tumor cell ALDH1 expression significantly correlated only with basal-like and HER2 tumor types in the adjuvant series and tumor grade in the neoadjuvant cohort. No significant enrichment for ALDH1 positive cells was observed in the postneoadjuvant therapy specimens compared to pretreatment samples. On the other hand, high degree of stromal expression was significantly associated with best disease-free survival as well as a trend for overall survival. The association of stromal expression was confirmed in an independent cohort of triple negative cases. The novel finding is that tumor microenvironment may play a significant role in determining the prognostic impact of stem/progenitor cells in human breast tumors.

Atypical ductal hyperplasia: interobserver and intraobserver variability

Interobserver reproducibility in the diagnosis of benign intraductal proliferative lesions has been poor. The aims of the study were to investigate the inter- and intraobserver variability and the impact of the addition of an immunostain for high- and low-molecular weight keratins on the variability. Nine pathologists reviewed 81 cases of breast proliferative lesions in three stages and assigned each of the lesions to one of the following three diagnoses: usual ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ. Hematoxylin and eosin slides and corresponding slides stained with ADH-5 cocktail (cytokeratins (CK) 5, 14. 7, 18 and p63) by immunohistochemistry were evaluated. Concordance was evaluated at each stage of the study. The interobserver agreement among the nine pathologists for diagnosing the 81 proliferative breast lesions was fair (κ-value=0.34). The intraobserver κ-value ranged from 0.56 to 0.88 (moderate to strong). Complete agreement among nine pathologists was achieved in only nine (11%) cases, at least eight agreed in 20 (25%) cases and seven or more agreed in 38 (47%) cases. Following immunohistochemical stain, a significant improvement in the interobserver concordance (overall κ-value=0.50) was observed (P=0.015). There was a significant reduction in the total number of atypical ductal hyperplasia diagnosis made by nine pathologists after the use of ADH-5 immunostain. Atypical ductal hyperplasia still remains a diagnostic dilemma with wide variation in both inter- and intraobserver reproducibility among pathologists. The addition of an immunohistochemical stain led to a significant improvement in the concordance rate. More importantly, there was an 8% decrease in the number of lesions classified as atypical ductal hyperplasia in favor of usual hyperplasia; in clinical practice, this could lead to a decrease in the number of surgeries carried out for intraductal proliferative lesions.

PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer

Aurora A kinase is overexpressed in the majority of breast carcinomas. A chemical genetic approach was used to identify the malignant targets of Aurora A, which revealed pleckstrin-homology-like domain protein PHLDA1 as an Aurora A substrate. PHLDA1 downregulation is a powerful prognostic predictor for breast carcinoma, which was confirmed in our study. We further show that downregulation of PHLDA1 is associated with estrogen receptor (ER) expression in breast carcinoma. Aurora A directly phosphorylates PHLDA1 leading to its degradation. PHLDA1 also negatively regulates Aurora A, thereby triggering a feedback loop. We demonstrate the underlying mechanisms by which PHLDA1 upregulation strongly antagonizes Aurora-A-mediated oncogenic pathways, thereby revealing PHLDA1 degradation as a key mechanism by which Aurora A promotes breast malignancy. Thus, not surprisingly, PHLDA1 upregulation acts synergistically with Aurora A inhibition in promoting cell death. PHLDA1 overexpression might therefore be an alternative method to modulate Aurora A deregulation in breast carcinoma. Finally, this study led to the discovery of a mutation in the Aurora A active site that renders it amenable to the chemical genetic approach. Similar mutations are required for Aurora B, suggesting that this modified approach can be extended to other kinases that have hitherto not been amenable to this methodology.

High-level expression of forkhead-box protein A1 in metastatic prostate cancer

Jain R K, Mehta R J, Nakshatri H, Idrees M T & Badve S S
(2011) Histopathology58, 766–772
High‐level expression of forkhead‐box protein A1 in metastatic prostate cancer

Personalized medicine: the road ahead.

With breast cancer now being recognized as a heterogeneous disease, the concept of personalized medicine demands that the tumor of every individual be treated uniquely. This has lead to ever-expanding use of existing prognostic and predictive markers, and the search for better ones is ongoing. The classic prognostic tools such as tumor size, lymph node status, grade, hormone receptors, and HER2 status are now supplemented by gene expression-based tools such as PAM50 and MammaPrint. However, the overdependence of these tools on proliferation-related genes is a significant handicap. Although pathway-based signatures hold great promise in future breast cancer prognostication, the fact that every tumor has multiple functional pathways significantly limits the utility of this approach. Developed by the integration of estrogen receptor (ER), HER2, proliferation-related, and other genes, the Oncotype DX assay has been able to provide valuable prognostic information for ER-positive tumors. Newer molecular markers based on cancer stem cells, single-nucleotide polymorphisms (SNPs), and miRNAs are becoming available, but their importance needs to be validated. It is clear that breast cancer is a multifaceted process and that none of the tools can reliably predict a binary outcome (recurrence or no recurrence). The breast cancer community is still awaiting an ideal prognostic tool that can integrate knowledge from classic variables such as tumor size and grade with new throughput technology and principles of pharmacogenomics. Such a tool will not only define prognostic subgroups but also be able to predict therapeutic efficacy and/or resistance based on molecular profiling.

Genomic and immunohistochemical analysis of adenosquamous carcinoma of the breast

Breast adenosquamous carcinomas are rare tumours characterized by well-developed gland formation intimately admixed with solid nests of squamous cells immersed in a highly cellular spindle cell stroma. A low-grade variant has been described that is associated with a better prognosis. Here we studied five cases of adenosquamous carcinomas to determine their genetic profiles and to investigate whether the spindle cell component of these cancers could at least in part stem from the glandular/epithelial components. Five adenosquamous carcinomas of the breast were subjected to (1) immunohistochemical analysis, (2) microdissection and genetic analysis with a high-resolution microarray comparative genomic hybridization platform, and (3) chromogenic in situ hybridization. All cases displayed a triple-negative immunophenotype, consistently expressed ‘basal’ keratins and showed variable levels of epidermal growth factor receptor expression. Microarray comparative genomic hybridization analysis of two of the cases revealed multiple low-level gains and losses affecting several chromosomal arms. Case 1 displayed gains of the whole of chromosome 7, and case 2 harboured a focal, high-level amplification of 7p12, encompassing the epidermal growth factor receptor gene, which was associated with strong and intense membranous epidermal growth factor receptor expression. Chromogenic in situ hybridization revealed that the genetic features found in the epithelial cells were also present in a minority of the spindle cells of the stromal component, in particular in those near the epithelial clusters, indicating that some of the spindle cells are clonal and derived from the epithelial component of the tumour. In conclusion, breast adenosquamous carcinomas are triple-negative cancers that express ‘basal’ keratins. These tumours harbour complex genetic profiles. Some of the spindle cells in adenosquamous carcinomas are derived from the epithelial component, suggesting that adenosquamous carcinomas may also be part of the group of metaplastic breast carcinomas with spindle cell metaplastic elements.

Extrathoracic metastases of thymic origin: a review of 35 cases.

Thymic tumors are categorized as types A, AB, B1, B2, B3, and thymic carcinoma under the World Health Organization (WHO) classification. Thymomas are typically slow growing tumors that predominantly involve the surrounding structures through direct invasion, while thymic carcinomas tend to be more aggressive. A significant number of patients are asymptomatic and can present with metastases as the first presentation. The exact incidence of extrathoracic metastases from thymoma is not known. This study describes a series of 35 cases of histologically documented metastatic thymomas and thymic carcinomas at extrathoracic sites. These cases were classified according to the current World Health Organization (WHO) classification criteria, and we present their clinical data as well as discuss the differential diagnoses of these lesions. Our study shows that all types of thymic tumors, regardless of histologic type, can be associated with invasion and metastases to thoracic and extrathoracic sites.

WHO types A and AB thymomas: not always benign

The 2004 WHO classification of thymic tumors recognizes five major subtypes of thymomas and thymic carcinoma. Subtypes A and AB thymomas are purported to be benign neoplasms, although prior studies have suggested a potential for malignant behavior. The purpose of this study was to assess the clinical behavior of A and AB thymomas identified from a large institutional pathologic database. A retrospective slide review of 500 thymic epithelial tumors identified 71 (∼14%) cases of types A and AB thymomas. Clinical history and follow-up information were obtained through retrospective chart review. There were 38 and 33 cases of types A and AB thymomas, respectively. Complete follow-up data were available in 37 (52%) cases. Eighteen (49%) patients (type A, n=9 and type AB, n=9) had evidence of recurrent/metastatic disease at an average of 62 months (range from 6 to 244 months) after initial diagnosis. Survival curves for patients with types A and AB thymomas, with and without recurrences, show a statistically significant difference (P=0.001 and 0.005, respectively). Analysis of this large cohort confirms the potential for subtypes A and AB thymomas to show malignant behavior. Long-term clinical monitoring, therefore, appears to be justified in these cases. This study also shows the poor correlation between the WHO classification and tumor behavior

Expression of high-molecular-weight cytokeratin (34βE12) is an independent predictor of disease-free survival in patients with triple-negative tumours of the breast

One-fifth of breast cancers have the triple-negative phenotype; a good prognostic marker has yet not been described for these tumours. Tumour microarrays from 58 triple-negative patients treated with surgery followed by chemotherapy were analysed for expression of cytokeratin 5/6 (CK5/6), epidermal growth factor receptor (EGFR), vimentin, p63 and cytokeratin 34βE12. The mean patient age was 59.2 years with a follow-up from 39 to 168 months. Clinicopathological variables and survival data were correlated with biomarker expression. The frequency of expression of cytokeratin 5/6, EGFR, vimentin, p63 and 34βE12 was 33%, 65%, 50%, 19% and 85%, respectively. Each of 34βE12, p63, EGFR and T stage significantly correlated with both disease-free survival and overall survival. T stage and 34βE12 were independent predictors of overall survival in a multivariate analysis. Expression of 34βE12 predicts disease-free and overall survival in patients with triple-negative tumours. Additional studies are planned to confirm these initial findings.

Cancer Survivorship and Models of Survivorship Care: A Review.

There are over 13 million cancer survivors in the United States. This is heterogenous group in age, cultural background, and cancer history and also in regards to the natural history of their cancer survivorship. There are “seasons of survivorship” including acute, transitional, extended, permanent, and chronic in which the medical and psychosocial problems and needs of cancer survivors change. For example, the medical and psychosocial needs of a testicular cancer survivor who is 1 year beyond diagnosis are very different from the same person 20 years later when the risk of recurrence is very low but the risk of second cancers has risen. This is a review of the “seasons of survivorship.” Some of the specific needs of cancer survivors in each phase of survivorship are presented. Models of survivorship care are also reviewed.