The power of an idea: Andrew Wyllie Lockshin, Richard A.; Cummings, Margaret C.
Cell death and differentiation,
09/2022, Letnik:
29, Številka:
9
Journal Article
Molecular classification of breast cancer Vuong, Darina; Simpson, Peter T.; Green, Benjamin ...
Virchows Archiv : an international journal of pathology,
07/2014, Letnik:
465, Številka:
1
Journal Article
Recenzirano
Breast cancer is a complex, multifaceted disease encompassing a great variety of entities that show considerable variation in clinical, morphological and molecular attributes. Traditional ...classifications including histological assessment and clinical staging are used to guide patient management. In recent years, there has been exponential progress in molecular analysis with profound implications for our understanding of breast cancer biology and, hence, classification. There are now genome-based frameworks for the molecular categorisation of breast cancer including the development of prognostic and predictive signatures that potentially allow individualisation of treatment. Here we review the current state of the molecular classifications of in situ and invasive breast cancer including special subtypes. Future perspectives are also provided.
The immune microenvironment of breast ductal carcinoma
(DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown.
We quantified tumor associated ...lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number (
= 55) and mutation data (
= 20).
TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%-90%). Most DCIS were negative for tumor cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high-grade (
= 0.002/0.035), ER-negative (
= 0.02/0.02), and
-amplified tumors (
< 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (
< 0.0001) but not with PD-L1. The TILs score was significantly higher in cases with
mutation (
= 0.03) but not with
or
mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both
< 0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels.
Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumor copy number with the immune microenvironment, possibly by the immunoediting of the tumor.
.
Introduction: Breast cancer is a heterogeneous disease, at morphological, molecular, and clinical levels and this has significant implications for the diagnosis and management of the disease. The ...introduction of breast screening, and the use of small tissue sampling for diagnosis, the recognition of new morphological and molecular subtypes, and the increasing use of neoadjuvant therapies have created challenges in pathological diagnosis and classification.
Areas covered: Areas of potential difficulty include columnar cell lesions, particularly flat epithelial atypia, atypical ductal hyperplasia, lobular neoplasia and its variants, and a range of papillary lesions. Fibroepithelial, sclerosing, mucinous, and apocrine lesions are also considered. Established and newer prognostic and predictive markers, such as immune infiltrates, PD-1 and PD-L1 and gene expression assays are evaluated. The unique challenges of pathology assessment post-neoadjuvant systemic therapy are also explored.
Expert opinion: Controversies in clinical management arise due to incomplete and sometimes conflicting data on clinicopathological associations, prognosis, and outcome. The review will address some of these challenges.
The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and ...the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P=0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P=0.005), including a significant positive association with amplification or gain of ERBB2 (P<0.05). The association between TP53 mutation and ERBB2 amplification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P=0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation.
Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with ...germline mismatch repair (MMR) gene mutations.
Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS).
Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered.
Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.
Periostin (POSTN), a secreted homodimeric protein that binds integrins αvβ3, αvβ5, and α6β4, was originally found to be expressed in fetal tissues and in the adult upon injury particularly bone ...fractures due to its role in remodelling and repair. Recently it was found to be over‐expressed in human breast cancer and a variety of other tumour types including head and neck squamous cell carcinoma, where its overexpression correlates with increased tumour invasion. Progress in studying its functional role in tumour pathogenesis has been hampered by the paucity of antibodies for its specific and sensitive detection. It has proven very difficult to obtain monoclonal antibodies (mAbs) against this highly conserved protein but we report here that combining infection of mice with lactate dehydrogenase elevating virus (LDV), a B cell activating arterivirus, with conjugation of human POSTN to ovalbumin as an immunogenic carrier, enabled us to develop six mAbs recognizing both human and mouse POSTN and inhibiting its binding to αvβ3 integrin. Two of the mAbs, MPB4B1 and MPC5B4, were tested and found to inhibit POSTN‐induced migration of human endothelial colony forming cells. All six mAbs recognized amino acids 136‐51 (APSNEAWDNLDSDIRR) within the POSTN fascilin (FAS) 1‐1 domain revealing the functional importance of this motif; this was further highlighted by the ability of aa 136–151 peptide to inhibit integrin‐mediated cell migration. Immunohistochemistry using MPC5B4, indicated that breast tumour cell POSTN expression was a strong prognostic indicator, along with tumour size, lymph node, and human epidermal growth factor receptor 2 (HER2) status.
What's new?
Periostin, a secreted glycoprotein involved in bone injury repair, has recently gained interest in the cancer field as it is overexpressed in several tumor types and binds to various integrins. Here, the authors developed neutralizing monoclonal antibodies against human periostin using a sophisticated immunization scheme. Their results point to periostin as a strong prognostic indicator in breast cancer tissue and a potential new therapeutic target in the prevention of cancer cell migration and adhesion.
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