Genetic Profiling Differentiates Second Primary Tumors from Metastases in Adult Metachronous Soft Tissue Sarcoma

Purpose. Patients with soft tissue sarcomas (STS) are at increased risk of second primary malignancies, including a second STS, but distinction between metastases and a second primary STS is difficult.Patients and Methods. Array-based comparative genomic hybridization (aCGH) was applied to 30 multiple STS of the extremities and the trunk wall from 13 patients. Different histotypes were present with malignant fibrous histiocytomas/undifferentiated pleomorphic sarcomas being the predominant subtype.Results. aCGH profiling revealed genetic complexity with multiple gains and losses in all tumors. In an unsupervised hierarchical cluster analysis, similar genomic profiles and close clustering between the first and subsequent STS were identified in 5 cases, suggesting metastatic disease, whereas the tumors from the remaining 8 patients did not cluster and showed only weak pairwise correlation, suggesting development of second primary STS.Discussion. The similarities and dissimilarities identified in the first and second STS suggest that genetic profiles can be used to distinguish soft tissue metastases from second primary STS. The demonstration of genetically different soft tissue sarcomas in the same patient suggests independent tumor origin and serves as a reminder to consider development of second primary STS, which has prognostic and therapeutic implications.

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EFFECTS OF SMOKING ON THE DISEASE PROGNOSIS IN CANCER PATIENTS

Problems in oncology ◽

10.37469/0507-3758-2019-65-3-321-329 ◽

2019 ◽

Vol 65 (3) ◽

pp. 321-329

Author(s):

David Zaridze ◽

Anush Mukeriya

Keyword(s):

Smoking Cessation ◽

Cancer Patients ◽

Malignant Tumors ◽

Scientific Data ◽

Second Primary ◽

Primary Tumors ◽

Smoking Intensity ◽

Risk Of Death ◽

Disease Prognosis ◽

Increased Risk

Smoking not only increases the risk of the development of malignant tumors (MT), but affects the disease prognosis, mortality and survivability of cancer patients. The link between the smoking of cancer patients and increased risk of death by all diseases and oncological causes has been established. Mortality increases with the growth of the smoking intensity, i.e. the number of cigarettes, smoked per day. Smoking is associated with the worst general and oncological survivability. The statistically trend-line between the smoking intensity and survivability was observed: each additional unit of cigarette consumption (pack/year) leads to the Overall Survival Reduction by 1% (p = 0.002). The link between smoking and the risk of developing second primary tumors has been confirmed. Smoking increases the likelihood of side effects of the antitumor therapy both drug therapy and radiation therapy and reduces the treatment efficacy. The smoking cessation leads to a significant improvement in the prognosis of a cancer patient. Scientific data on the negative effect of smoking on the prognosis of cancer patients have a major clinical importance. The treatment program for cancer patients should include science-based methods for the smoking cessation. The latter is fundamentally important, taking into account that the smoking frequency among cancer patients is much higher than in the population.

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Sarcomas of Soft Tissue and Bone

10.2310/im.1187 ◽

2011 ◽

Author(s):

Adam Lerner ◽

Huihong Xu ◽

Karen H Antman

Keyword(s):

Soft Tissue ◽

Meta Analysis ◽

Survival Rates ◽

Fibrous Tissue ◽

Soft Tissue Sarcomas ◽

Kaposi Sarcoma ◽

Uterine Leiomyosarcoma ◽

Increased Risk ◽

Bone Sarcomas ◽

Epidemiologic Features

Sarcomas originate from bone or soft tissue. The most common bone sarcomas are osteosarcomas, Ewing sarcomas, and chondrosarcomas. Soft tissue sarcomas develop in fibrous tissue, fat, muscle, blood vessels, and nerves. Historically, soft tissue sarcomas of the trunk and extremities were reported separately from those of visceral organs (e.g., gastrointestinal and gynecologic sarcomas). This chapter discusses the classification, epidemiology, diagnosis, staging, and treatment of sarcomas of bone and cartilage, and classic soft tissue sarcomas. Management of Kaposi sarcoma, gastrointestinal stromal tumors (GISTs), mesothelioma, and rhabdomyosarcoma is also described. Figures include images of patients with osteosarcoma, liposarcoma, uterine leiomyosarcoma, GIST, and osteosarcoma in a patient with Paget disease of bone. Tables list epidemiologic features of sarcomas, a summary of sarcomas by histology, familial syndromes associated with increased risk of sarcoma, survival rates in sarcoma patients, staging of soft tissue sarcomas, and results of a meta-analysis of doxorubicin-based adjuvant chemotherapy for localized resectable soft tissue sarcoma. This chapter contains 126 references.

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Focus on the Tumour Periphery in MRI Evaluation of Soft Tissue Sarcoma: Infiltrative Growth Signifies Poor Prognosis

Sarcoma ◽

10.1155/srcm/2006/21251 ◽

2006 ◽

Vol 2006 ◽

pp. 1-5 ◽

Cited By ~ 20

Author(s):

Josefin Fernebro ◽

Marie Wiklund ◽

Kjell Jonsson ◽

Pär-Ola Bendahl ◽

Anders Rydholm ◽

...

Keyword(s):

Soft Tissue ◽

Growth Pattern ◽

Tumour Growth ◽

Neoadjuvant Treatment ◽

Soft Tissue Sarcomas ◽

Prognostic Information ◽

Diffuse Infiltration ◽

Increased Risk ◽

Tumour Periphery ◽

Mri Evaluation

Purpose. Infiltrative microscopical peripheral growth of soft tissue sarcomas (STS) has been shown to be of prognostic importance and preoperative risk stratification could individualize neoadjuvant treatment.Patients and methods. We assessed peripheral tumour growth pattern on preoperative MRI from 78 STS. The findings were correlated to histopathology and to outcome.Results. The MRI-based peripheral tumour growth pattern was classified as pushing in 34 tumours, focally infiltrative in 25, and diffusely infiltrative in 19. All tumours with diffuse infiltration on MRI also showed microscopical infiltration, whereas MRI failed to identify infiltration in two-thirds of the microscopically infiltrative tumours. Diffusely infiltrative growth on MRI gave a 2.5 times increased risk of metastases (P=.01) and a 3.7 times higher risk of local recurrence (P=.02).Discussion. Based on this observation we suggest that MRI evaluation of STS should focus on the peripheral tumour growth pattern since it adds prognostic information of value for decisions on neoadjuvant therapies.

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Genomic index in pediatric synovial sarcoma (SYNOBIO study): The European Pediatric Soft Tissue Sarcoma Group (EpSSG) experience.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.10529 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 10529-10529

Author(s):

Daniel Orbach ◽

Veronique Mosseri ◽

Daniel Pissaloux ◽

Bernadette Brennan ◽

Andrea Ferrari ◽

...

Keyword(s):

Prognostic Factor ◽

Soft Tissue ◽

Synovial Sarcoma ◽

Soft Tissue Sarcomas ◽

Fusion Transcript ◽

Risk Groups ◽

Comparative Genomic ◽

Perioperative Therapy ◽

Free Survival ◽

Flat Profile

10529 Background: A genomic index (GI) tool using array comparative genomic hybridization (aCGH) on tumor cells has recently been developed, and shown a high prognostic value in adult soft tissue sarcomas. GI correlates with genomic instability, and has emerged as independent prognostic factor associated with the risk of metastases developing in synovial sarcoma (SS). The aim, therefore, was to assess GI in pediatric patients with SS, to assess its value as a prognostic factor and its role in risk stratification. Methods: All pediatric/adolescent/young adults’ (<25 years) with localized SS prospectively included in the European EpSSG-NRSTS05 protocol with a contributive aCGH were selected. Tumors had a central pathological review or harbored the specific fusion transcript (SYT-SSX). Definition of GI was A2/C, where A is the total number of alterations (segmental gains and losses) and C is the number of involved chromosomes on aCGH results. GI1 group corresponds to cases with no or few alterations (flat profile, GI≤1) and GI2 group cases with many alterations (complex CGH profile; GI>1). Results: A total of 48 patient’s samples were available. The median age of the cohort was 13 years (range: 4-24). Patients received surgery only (19%), with adjuvant therapy (17%) or perioperative therapy (64%). GI1 group corresponded to 54.2%, and GI2 to 45.8%. After a median follow up of 58 months (range: 0.1-107), 10 tumor events occurred and 5 patients died. Patients with high GI have more axial (P<0.01), invasive (P=0.04) and higher therapeutic risk groups’ tumors (unresectable/axial tumors; P<0.015). Respectively for GI1 vs. GI2 groups, 5-year event free survival (EFS) rates were 91.8±5.6% vs. 58.9±11.2% (P<0.0084) and 5Y-Metastatic Free Survival 91.8±5.5% vs. 68.6±10.6% (P=0.055). In multivariate analysis, GI adjusted for IRS groups, site and tumor size remains prognostic for EFS (P<0.025). Conclusions: Although tumor events were rare for SS in NRSTS 2005, high GI selected patients with high risk tumor features and predicted a poorer outcome. GI may explain aggressive behavior of some pediatric SS. Founding sources: “Enfant-et-santé/SFCE,” “Info sarcome,” and “La ligue contre le cancer.”

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Second Primary Tumors in Neurofibromatosis 1 Patients Treated for Optic Glioma: Substantial Risks After Radiotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.8349 ◽

2006 ◽

Vol 24 (16) ◽

pp. 2570-2575 ◽

Cited By ~ 210

Author(s):

Saba Sharif ◽

Rosalie Ferner ◽

Jillian M. Birch ◽

James E. Gillespie ◽

H. Rao Gattamaneni ◽

...

Keyword(s):

Nervous System ◽

Neurofibromatosis 1 ◽

Optic Glioma ◽

Second Primary ◽

Primary Tumors ◽

Nervous System Tumors ◽

Increased Risk ◽

Second Tumors

Purpose Optic pathway gliomas (OPGs) are the most common CNS tumor in neurofibromatosis 1 (NF1) patients. We evaluated the long-term risk of second tumors in NF1-related OPGs after radiotherapy. Patients and Methods We reviewed 80 NF1 OPG patients from two NF1 clinics to evaluate the long-term risk of developing subsequent nervous system tumors, with or without radiotherapy. Results Fifty-eight patients were assessable for second tumors. Nine (50%) of 18 patients who received radiotherapy after their OPGs developed 12 second tumors in 308 person-years of follow-up after radiotherapy. Eight (20%) of 40 patients who were not treated with radiotherapy developed nine tumors in 721 person-years of follow-up after diagnosis of their OPGs. The relative risk of second nervous system tumor after radiotherapy was 3.04 (95% CI, 1.29 to 7.15). Conclusion There is a significantly increased risk of second nervous system tumors in those NF1 patients who received radiotherapy for their OPGs, especially when treated in childhood. Thus radiotherapy should only be used if absolutely essential in children with NF1.

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Terminal phase in patients (pts) with advanced sarcomas: A perspective study for a better assistance

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9551 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9551-9551

Author(s):

A. Comandone ◽

C. Oliva ◽

A. Boglione ◽

F. Garetto ◽

P. Bergnolo ◽

...

Keyword(s):

Soft Tissue ◽

Supportive Care ◽

Soft Tissue Sarcomas ◽

Psychological Needs ◽

Local Relapse ◽

Terminal Phase ◽

Primary Tumors ◽

Bone Sarcomas ◽

Few Data ◽

Control Pain

9551 Background: Sarcoma are rare tumors, with an incidence <1% of all neoplasms. Very few data are available on the clinical and psychological needs of the pts in terminal phase of these diseases. In terminal phase the goal is no more cure or prolongation of life, but the control of symptoms related to the disease progression. Methods: As a specialized interdisciplinary group we have started to treat the pts afflicted from soft tissue and bone sarcomas since 1994. We have recorded in a perspective study the problems of the terminal pts from 1998 until 2005. We have followed 178 pts with sarcomas in terminal phase for at least 3 months: 95 males and 83 females, median age 57 years, median PS 50 Karnofsky. Histologically 143 had soft tissue sarcomas, 28 osteosarcomas, 7 Ewing sarcomas. Extremities were the origin of the disease in 33.7% of the cases, abdomen in 29.2%, trunk in 21.9% and other sites in 15.2%. Site of recorded metastases: lung 48.3%, liver 18.5%, bone 15.7%, brain 7.9%, nodes 4.5%. Inoperable primary tumors or local relapse 30.9%. Results: During the last part (1 months) of their lives the pts complained with: pain 78.7%, dyspnoea 48.9%, anxiety 16.9%, gastrointestinal obstruction 24.7%, anorexia 51.1%, bleeding 7.9%. 57.3% of these pts died at home, 42.7% at the hospital. To control pain, dyspnoea and the other symptoms radiotherapy (43%), supportive care (100%) and palliative chemotherapy (36%) were used. Psycological support was offered to the majority of pts (63.5%) as well as physical rehabilitation (56.8%). Conclusions: Supportive care of pts with advanced sarcomas is an underestimated aspect in clinical oncology. We have demonstrated that these pts have specific needs, on some aspects, different from those of the pts afflicted from the most common cancers. A complex, multidisciplinary approach is necessary in order to improve the assistance and quality of life of these pts. No significant financial relationships to disclose.

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Impact of immune checkpoint and BRAF inhibitors on the incidence of second primary malignancies (SPM) in melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.12061 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 12061-12061

Author(s):

Nibash Budhathoki ◽

Sunita Timilsina ◽

Prashanti Atluri ◽

Jeffrey S. Weber ◽

Marc Justin Braunstein

Keyword(s):

Immune Checkpoint ◽

Absolute Risk ◽

Incidence Rates ◽

Advanced Melanoma ◽

Second Primary ◽

Braf Inhibitors ◽

Calendar Time ◽

Small Bowel Tumors ◽

Primary Tumors ◽

Increased Risk

12061 Background: Prior studies have shown an increased risk of SPM in melanoma, however there is limited data on the incidence of SPM following the 2011 approvals of immune checkpoint (ipilimumab) and BRAF (vemurafenib) inhibitors, which have become standard of care. We present data comparing SPM rates before and after introduction of these agents for advanced cutaneous melanoma. Methods: Adult melanoma patients with regional or distant metastases were identified from SEER-18 database and divided into cohorts: 2005-2010 and 2011-2016. SPM was defined as tumors diagnosed ≥6 months from diagnosis of the primary cancer. SEER*stat was used to calculate SPM by multiple primary standardized incidence ratio based on observed (O) and expected (E) cases. The expected numbers of new cancers of specific types were estimated by assuming that incidence rates for new primary tumors corresponded to sex, age, and calendar time–specific SEER rates for similar invasive primary cancers and applying those rates to the accumulated person-years (PYR) of observation. Excess absolute risk (EAR) of malignancy per 10,000 PYR at risk was calculated as ([O − E]/PYR) × 10,000. Results: As shown in the table, from before 2005-2010, 421 of 7991 patients (5.2%) with advanced melanoma had 444 SPM (O/E ratio 2.2, 95% CI 1.9-2.4, P < 0.0001, EAR 157). In comparison, from 2011-2016, 527 of 9341 patients (5.6%) developed 584 SPM (O/E ratio 2.5, 95% CI 2.3-2.7, P < 0.0001, EAR 193). Incidence of AML, myeloma, and pancreatic cancer increased in 2005-2010, while soft tissue malignancies increased from 2011-2016. The incidence of thyroid, brain, and small bowel tumors increased in both groups from 2005-2016. Conclusions: There is a distinct pattern as well as increased latency of SPM in patients with advanced melanoma in the era of immune checkpoint and BRAF inhibitors. We speculate that reduction in chemotherapy use, augmentation of immunosurveillance, and inhibition of oncogenic pathways may impact the pathogenesis of SPM. [Table: see text]

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Germline mutations in MSH2 and ATM gene in patients with GIST (gastrointestinal stromal tumor) and second epitelial tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e23520 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e23520-e23520

Author(s):

Silvia Gasperoni ◽

Laura Papi ◽

Francesca Castiglione ◽

Francesca Gensini ◽

Roberta Sestini ◽

...

Keyword(s):

Genetic Counseling ◽

Lynch Syndrome ◽

Colon Adenocarcinoma ◽

Germline Mutations ◽

Genetic Alterations ◽

Second Primary ◽

Sequencing Analysis ◽

Msh2 Gene ◽

Primary Tumors ◽

Therapeutic Implications

e23520 Background: In adult GISTs are frequently sporadic, while rarely GISTs are linked to Carney Triad and Carney-Stratakis Syndrome and NF1. GISTs with second primary tumors are reported in 4-33% of patients in literature and genetic counseling is suggested to explore an underlying germline mutations pathway. Methods: In our Academic Hospital Centre (EURACAN member) in Florence, Italy, we are following patients with GIST and multiple primary tumors with genetic counseling (72 GISTs with second tumors/185 patients with GIST) and germline analysis of the following genetic panel is performed as clinically indicated: BRCA1, BRCA2, MUTYH, MLH1, MSH2, MSH6, CDH1, ATM, TP53, PTEN, CHECK2, PALB2, BARD1, BRIP1, BLM, RAD51C, RAD51D, XRCC2, PMS2, MRE11A, RAD50, NBN, FAM175A, EPKAM, TSK1, MEN1 by sequencing analysis with Illumina MiSeq by kit multiplicom BRCA Hereditary cancer Mastr plus, and bioinformatic analysis by software SOPHIADDM (Sophia genetics) for point genetic alterations of BRCA1 NM_007294.3, BRCA2 NM_000059.3, MUTYH NM_000249, MSH2 NM_000251, MSH6 NM_000179, CDH1 NM_00444360, ATM NM_000051, TP53 NM_000546, PTEN NM_000314, CHEK2 NM_001005735, PALB2 NM_024675, BARD1 NM_000465, BRIP1 NM_032043, BLM NM_000057, RAD51C NM_002876, RAD51D NM_001142571, XRCC2 NM_005431, PMS2 NM_000535, MRE11A NM_005590, RAD50 NM_006732, NBN NM_002485, FAM175A NM_139076, EPCAM NM_002354, STK1 NM_000455, MEN1 NM_000244 and MLPA (Multiplex Ligation-dependent Probe Amplification) test analysis for patients with kit P087-BRCA1,P045-BRCA2(CHEK2, P248-MLH1-MSH2, P003-MLH1/MSH2, P072-MSH6-MUTYH (MRC-Holland). Results: In 3 patients germline mutations have been observed: 1 patient showed the c.1192dupG, p.(Ala398Glyfs*19) pathogenic mutation in exon 7 of MSH2 gene, confirmed by Sanger Sequencing, 1 patient showed c.565-?_1130+?del mutation consisting in heterozygous 3-4-5-6 exons deletion of MSH2 gene, confirmed by MLPA analysis, and in 1 patient the following ATM alteration has been identified in heterozygosis: ATM c.5319+2T > C, p.(?). In the 2 patients with Lynch syndrome with colon adenocarcinoma (MSI-H), synchronous GISTs (1 patient quadruple WT and 1 patient kit ex 11 mutated ) were diagnosed; in the patient with ATM mutation, the diagnosis of GIST (kit ex 11 mutated) occurred after prostate adenocarcinoma and before colon adenocarcinoma (MSI-H). Conclusions: Our analysis suggests that GIST diagnosis could be tumor-related to multiple hereditary tumor syndromes as Lynch Syndrome and Ataxia-Teleangectasia syndrome, the latter being linked in eterozygosis to tumor susceptibility to breast in female. This report represents a high value in terms of genetic counseling for relatives and in terms of therapeutic implications for the patients.

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