Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Irradiation of the chest-wall and supraclavicular fossa

Radiotherapy

Eduardo Rosenblatt, MD

Eeva K. Salminen, Section Head

Jorge M. Marinello, MD

Magda M. El-Mongy, MD

Ahmed Elzawawy, MD

Ahmed Elsawawy, MD

Verna Vanderpuye, MD

Mansouri Aziz, MD

Oladapo B. Campbell, MD

Safoora Shahid, MD

Jorge A. Moscol_Ledesma, MD

Jorge A. Moscol-Ledesma, MD

Nuran Bese, MD

This study compares two different field set-ups in patients with breast cancer following a breast resection (mastectomy). These two set-ups are as follows: arm a - radiotherapy to the chest-wall only, and arm b - radiotherapy to the chest-wall and the supraclavicular fossa.

Patients in both treatment arms will receive radiotherapy with a shortened fractionation schedule.

Study hypothesis: irradiation of the chest-wall only is not inferior to irradiation of the chest-wall and supraclavicular fossa in terms of loco-regional control, survival and treatment toxicity.

Post-mastectomy radiotherapy (PMRT) substantially reduces the risk of loco- regional failure as shown in several studies and meta-analyses. Two large trials for pre-menopausal node-positive breast cancer patients treated with mastectomy and chemotherapy showed that PMRT not only reduced loco- regional failure rates but also improved disease-free and overall survival rates.

Although the benefit of PMRT is clear, the optimal volume of tissues to be covered by the radiotherapy fields is controversial. Since the chest wall is the most likely location of recurrence, there is uniform consensus that the chest wall should be irradiated. However, areas of controversy exist regarding irradiation of the regional lymph nodes (axillary, supraclavicular and internal mammary lymph nodes), optimal radiation dose, and dose-fractionation.

If equivalent results could be achieved by omitting irradiation of the supraclavicular region in patients receiving adjuvant systemic therapy, this will simplify and expedite treatment in this patient population. Furthermore, the use of a shortened fractionation schedule of 40 Gy in 15 fractions (2.67 Gy per fraction) over 3 weeks which has been used in the UK and Canada for post-mastectomy patients for several decades will shorten the duration of treatment by reducing the number of patient visits for radiotherapy and increase the number of patients who can be treated. Treatment will be more convenient for patients and a reduction in the number of treatments could result in savings for strained health care systems.

This is a randomized comparison of two different radiotherapy field set-ups for post-mastectomy treatment of locally advanced breast cancer. Patients who have undergone modified radical mastectomy including axillary lymph node dissection will be randomized to receive one of two radiotherapy treatment arms, A and B following the completion of adjuvant chemotherapy. The radiotherapy for treatment Arm A consists of irradiation of the chest wall only while Treatment Arm B includes irradiation of the chest wall and the ipsilateral supraclavicular field. Patients on both treatment arms will receive radiation with a shortened fractionation schedule. Patients will be evaluated for local control, regional control, survival and treatment toxicity.

Resource-sparing Post-mastectomy Radiotherapy in Breast Cancer

Resource-sparing Radiotherapy for Breast Cancer

The presence/absence of recurrent disease in the surgical scar, ipsilateral chest wall, ipsilateral skin and soft tissue.

The presence/absence of recurrent disease in the axilla, ipsilateral supraclavicular/infraclavicular nodes and or ipsilateral skin/soft tissue in the regional areas.

During treatment and up to 90 days following the completion of treatment.

More than 90 days after the completion of radiation therapy.

Number of pregnancies, miscarriages. Menstrual History.

International Network for Cancer Treatment and Research

International Atomic Energy Agency

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

Herbal and Botanical

All Drugs and Chemicals

Chrysanthemum

immunohistochemical determinations: Cell of Origin (COO) (according with Hans algorithm), evaluation of Cluster of Differentiation (CD) (CD20, CD5, CD10), Bcl6, Bcl2 (cut off\>50%), MUM1/IRF4, c-myc (cut off\>40%) and Ki67, FISH for c-myc and if rearranged for Bcl2 e Bcl6.

mRNA expression by Nanostring Single cell analysis Immune checkpoint expression Proteomic analysis Metabolic analysis

molecular characterization

Oriana Nanni, Dr

Bernadette Vertogen, Dr

Gerardo Musuraca, MD

Monica Tani, MD

Elena Sabbatini, MD

Annalia Molinari, MD

This is a prospective observational study. The primary objective is to identify new prognostic biomarkers for DLBCL patients in terms of progression-free survival (PFS) and able to add predictive capacity to recognized important clinical factors.

The secondary objectives are:

* to identify new biomarkers associated with overall survival (OS) and objective response rate (ORR)
* to characterize tissue and circulating immune microenvironment of DLBCL patients by bulk and single cell transcriptomics;
* to assess the correlation between the expression of immune checkpoint genes and mRNA signature;
* to describe the mutational status of a panel of genes relevant to DLBCL pathogenesis;.
* to assess the correlation between protein expression, mutational status and the messenger RNA (mRNA) signature.

For each enrolled patient, immunohistochemical determinations will be performed: Cell of origin (COO) (Germinal Cell -GC- or activated B-cell - ABC- type according with Hans algorithm ), evaluation of cluster of differentiation antigen 20 (CD20), cluster of differentiation antigen 5 (CD5), cluster of differentiation antigen 10 (CD10), Bcl6, Bcl2 (cut off\>50%), Multiple Myeloma 1 / Interferon Regulatory Factor 4 protein (MUM1/IRF4), c-myc (cut off\>40%) and Ki67, fluorescence in situ hybridization (FISH) for c-myc and if rearranged, for Bcl2 e Bcl6 ). Moreover, paraffin embedded (FFPE) tumor specimens will be collected for RNA extraction and mRNA expression analysis and sent to Bioscience Laboratory of Istituto Scientifico Romagnolo per lo studio e la cura dei tumori (IRST-IRCCS).

Diffuse large B-cell lymphoma (DLBCL) is an heterogeneous group of cancers classified together on the basis of morphology, immunophenotype, genetic alterations and clinical behavior. The distinction of DLBCL into cell-of origin (COO) categories, based on patterns of gene expression reminiscent ( germinal center B-cell- the GC group and activated B-cell- the ABC group-), as defined and characterized by the Lymphoma \& Leukemia Molecular Profiling Project (LLMPP), has profound biological, prognostic and potential therapeutic implications and in addiction, the negative prognostic effect of myelocytomatosis oncogene (MYC), B-cell lymphoma 2 (BCL2) and B-cell lymphoma-6 (BCL6) alterations in DLBCL has been showed largely dependent on COO subtypes . Furthermore, the combination of BCL2, MYC and BCL6 alterations with IPI (International Prognostic Index), identifies markedly worse prognostic groups within individual COO subtypes. The original methods used to define these entities, performed gene expression profiling (GEP) using microarrays on RNA derived from frozen tissue (FT). Subsequently, in an attempt to determine COO in standard practice using commonly available formalin-fixed paraffin-embedded tissue (FFPE) less precise but relatively inexpensive binary immunohistochemical (IHC) methods has been used . However in particular in non GC, the rate of concordance was unsatisfactory. A high degree of agreement has been demonstrated instead in COO determining, with a signature of 20 genes from formalin-fixed paraffin embedded (FFPE) tumor specimens, with Lymph2Cx kit (nCounter® Technology, NanoString Technologies), becoming the gold standard suggested in World Health Organization (WHO) classification . However recently, was demonstrated that the COO and BCL2, MYC, BCL6 status are not enough to describe the molecular risk of these patients, suggesting a genetic substructure that still to be discovered . Moreover, the tumor microenvironment and in particular the ratio of immune effectors and checkpoint molecules also have a prognostic role in DLBCL. Besides, elevated frequency of myofibroblasts, dendritic cells, and cluster of differentiation 4 (CD4) positive T cells correlated with better outcomes.

In conclusion, a comprehensive genomic analysis of these patients and a deep characterization of the immune compartment and immune checkpoints (Nanostring, immunohistochemistry for BCL2, MYC, BCL6, mutation analysis, proteomic analysis etc.) joined with IPI score, will allow the creation of a mixed, molecular, clinical, index (MMCI) to identify extremely poor prognostic groups, within each COO subtype, to consider a risk-adapted treatments in future.

It is a prospective observational study with a total duration of 36 months. The primary objective is the identification of new prognostic biomarkers for DLBCL patients in terms of progression-free survival (PFS) and able to add predictive capacity to recognized important clinical factors.

The secondary objectives are:

* to identify new biomarkers associated with overall survival (OS) and objective response rate (ORR);
* to characterize tissue and circulating immune microenvironment of DLBCL patients by bulk and single cell transcriptomics;
* to assess the correlation between the expression of immune - checkpoint genes and mRNA signature;
* to describe the mutational status of a panel of genes relevant to DLBCL pathogenesis;.
* to assess the correlation between protein expression, mutational status and the mRNA signature.

For each enrolled patient, immunohistochemical determinations will be performed by each Pathology Unit: COO (GC o ABC type according with Hans algorithm ), evaluation of CD20, CD5, CD10, Bcl6, Bcl2 (cut off\>50%), MUM1/IRF4, c-myc (cut off\>40%) and Ki67, FISH for c-myc and if rearranged, for Bcl2 e Bcl6). Moreover, paraffin embedded (FFPE) tumor specimens will be collected for RNA extraction and mRNA expression analysis and centralised at IRST-IRCCS.

Formalin fixed Paraffin embedded (FFPE) tumor specimens and peripheral blood samples.

Mixed Molecular Clinical Index (MMCI) in Diffuse Large B-cell Lymphoma (DLBCL)

To identify new prognostic biomarkers for DLBCL patients that combined to clinical factors (IPI) are able to create a MMCI, predictive in terms of progression-free survival (PFS) of DLBCL patients.

to identify molecular and clinical parameters associated with overall survival (OS) and objective response rate (ORR)

to characterize tissue and circulating immune microenvironment by bulk and single cell transcriptomics

to assess the correlation between the expression of immune checkpoint genes and mRNA signatures

describe the mutational status of a panel of genes relevant to DLBCL pathogenesis

assess the correlation between protein expression, mutational status and the mRNA signatures.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Resource-sparing Post-mastectomy Radiotherapy in Breast Cancer	NCT01452672	Breast Cancer	Radiotherapy Irradiation of ...	18 Years - 81 Years	International Atomic Energy Agency
Resource-sparing Post-mastectomy Radiotherapy in Breast Cancer	NCT01452672	Breast Cancer	Radiotherapy Irradiation of ...	18 Years - 81 Years	International Atomic Energy Agency
Mixed Molecular Clinical Index (MMCI) in Diffuse Large B-cell Lymphoma (DLBCL)	NCT04300101	Diffuse Large B...	molecular chara...	18 Years -	Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
Mixed Molecular Clinical Index (MMCI) in Diffuse Large B-cell Lymphoma (DLBCL)	NCT04300101	Diffuse Large B...	molecular chara...	18 Years -	Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
Mixed Molecular Clinical Index (MMCI) in Diffuse Large B-cell Lymphoma (DLBCL)	NCT04300101	Diffuse Large B...	molecular chara...	18 Years -	Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Spots Global Cancer Trial Database for molecular characterization