At the crossroads of molecular biology, pathology and the clinic

Abstract

This article outlines some of the highlights of the fourth ESMO Conference on Sarcoma and GIST, a broad-based international multidisciplinary educational meeting that focused on recent advances made in molecular biology and genetics, and the state-of-the art diagnosis and treatment of soft tissue sarcoma and gastrointestinal stromal tumors.

Keywords::

• biology
• genetics
• GIST
• soft tissue sarcomas
• treatment

The European Society for Medical Oncology (ESMO) was founded in 1975 and is, by definition, “the leading European professional organization committed to advancing the specialty of medical oncology and promoting a multidisciplinary approach to cancer treatment and care” [101]. Among its missions, disseminating oncological knowledge, and providing education and training have a major role. The fourth ESMO Conference on Sarcoma and GIST was organized in Milan on 9–10 March 2012 by a faculty committee headed by Paolo G Casali (Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy), A Paolo Dei Tos (General Hospital of Treviso, Treviso, Italy) and Jean-Yves Blay (Centre Léon Bérard, Lyon, France) and – under the engaging title “At the crossroads of molecular biology, pathology and the clinic” – it is a perfect example of the society’s successful activity. The meeting provided a wide-ranging and up-to-date overview on current medical therapy for soft tissue sarcomas and gastrointestinal stromal tumors (GIST), and on the related biological research currently underway. The various multidisciplinary sessions were arranged in an original way, based on the different anatomical regions where sarcomas can occur, from the classical limb locations to visceral or retroperitoneal, head and neck or thoracic sites. An audience of more than 400 people listened to talks presented by top-level international experts from the sarcoma community, and the key focus was on taking a multidisciplinary approach, including not only biological and clinical aspects, but also the patient’s perspective.

Sarcomas and GIST warrant a dedicated training effort for several reasons: because they are rare, but life-threatening; because they are often difficult to diagnose and their treatment is always a challenge; because their rarity often makes clinical trials unfeasible; and because they are particularly suitable as models for testing innovative therapies.

Two main sessions at the conference were dedicated to GIST. From a histopathological standpoint, the diagnosis of GIST relies on morphology (the epithelioid or spindle cell variant) and immunohistochemistry (DOG1, KIT, CD34 and PDGF receptor-α are positive in 98, 95, 70 and 80% of patients with GIST, respectively) [1]. Several spindle cell neoplasms need to be considered in the differential diagnosis, but specific immunohistochemical patterns facilitate diagnosis (i.e., β-catenin in aggressive fibromatosis, LSD1 in solitary fibrous tumor, melanocytic markers such as HMB45 and SMA in perivascular epithelioid cell tumors [PEComa], vascular markers in angiosarcoma, and CDK4 and MDM2 in liposarcoma). Most GISTs are caused by oncogenic mutations of the KIT and PDGFRA genes, which encode receptor tyrosine kinases. Biological analyses have been published detailing the pattern of these mutations in a few series of very small lesions (the so-called ‘microGISTs’) [2]. Deleterious mutations (e.g., KIT exon 11 mutations) are expressed in microGISTs as well, albeit less frequently than in clinical GISTs, although it has been suggested that further oncogenic mechanisms are needed to progress towards clinical GIST (chromosome deletions and SCF production by normal smooth muscle cells, among others).

As for the clinical aspects of GIST, the optimal approach to the care of these patients at all stages of their disease was illustrated, highlighting how rapidly the standards of practice have been changing as our biological understanding of the disease has increased [3–5]. An interesting discussion focused on how to predict the risk of recurrence, which is a crucial issue when it comes to deciding whether or not to opt for the adjuvant use of imatinib. Three main classifications for risk prediction purposes have been proposed (the NIH Consensus Criteria, the Modified NIH Consensus Criteria and the Armed Forces Institute of Pathology Criteria) that consider mitotic rate, tumor size and tumor site as risk factors. Although these algorithms enable high-risk patients and those at low or very low risk to be identified, novel variables such as tumor rupture, genotype and necrosis may be included in future systems for a more accurate assessment of the risk and a consequently better-customized treatment [6].

Except for cases of GIST with the D842V-PDGFRA mutant, imatinib is the standard treatment for advanced disease, achieving a median overall survival of 5 years and a median progression-free survival of 2 years [7,8]. Sunitinib is used for second-line, targeted therapy, succeeding in controlling disease for only a limited period (27 weeks was the time to progression in a Phase III trial) [9]. The experts have stressed the heterogeneity of secondary resistance mechanisms in GIST, and particular attention has been paid to the diverse genotypes coinciding with progressive disease and to the need for new strategies (i.e., a combination of targeted therapies) or new drugs aimed at new targets (i.e., BRAF, PI3K, IGF-1 receptor or mTOR pathways) [10].

The audience’s attention was then turned to the subject of soft tissue sarcomas, another scenario that – such as in the case of GIST – has been changing rapidly in the past few years. For a start, we have entered the era of the genome, with consequent significant additions to our knowledge of tumorigenesis, as well as numerous changes in our diagnostic procedures and criteria. We are also moving into the era of histology-driven therapy. It would now be safe to say that soft tissue sarcomas are rapidly evolving biological entities with a broad spectrum of sometimes overlapping morphological, biological and genetic features. Pathologists have shown that diagnosing sarcoma should be seen as an integrative activity that combines elements of histology, molecular biology and genetics. Speakers at the conference presented new insights derived from genome and expression profiling, shedding light on chromosomal complexities, and reported on new tools for prognostication and for orienting therapeutic decisions [11].

The audience learned that sarcomas differ and therefore require different treatments according to their histology and molecular biology; the trend is towards a therapy tailored to each patient. Various chemotherapies other than the classic ifosfamide–doxorubicin regimen have revealed significant activity in particular sarcoma subtypes, such as taxanes in angiosarcoma, gemcitabine and docetaxel in leiomyosarcoma, and trabectidine in myxoid liposarcoma [12]. The field of sarcoma is an ideal setting for making new discoveries and drug developments: the product of the specific chromosomal translocation occurring in sarcomas, and the different specific molecular pathways identified, are promising targets for potentially effective novel drugs [13]. A large number of targeted pathway inhibitors have been selected and tested in Phase I trials, and more will appear in the future. Imatinib has proved effective against dermatofibrosarcoma protuberans, chordoma and desmoid-type fibromatosis, as well as in pigmented villonodular synovitis (tenosynovial giant cell tumor); mTOR inhibitors (sirolimus) have been found to be active in PEComa [14], and so have multiple-kinase inhibitors in solitary fibrous tumor (sunitinib and sorafenib), alveolar soft part sarcoma (sunitinib and cediranib), and clear cell sarcoma (sunitinib and sorafenib). Maintenance therapy with pazopanib or ridaforolimus may have a role in some histotypes [15]. The complexity of the genomics of sarcoma nonetheless makes the imatinib in GIST model by no means easy to apply to most sarcoma histotypes, which often have multiple, heterogeneous molecular and functional aberrations. The main difficulty lies in pinpointing the signaling pathways that are crucial to the tumor’s development (driver vs passenger mutations); however, blocking these crucial pathways may induce the tumor cell to activate bypass feedback pathways and a consequent drug resistance. It is therefore fundamentally important to aim for the simultaneous inhibition of multiple targets, so as to intercept both the driver pathway and its bypass feedback pathway. Functional genomic tools may be of great help when it comes to choosing combination therapies [16].

A very interesting and broad-based session focused on retroperitoneal sarcomas, a peculiar subset of rare sarcomas – mainly liposarcomas and leiomyosarcomas – that generally feature a poor long-term outcome as a result of local and regional failures relating to the particular anatomical site of origin. An intensive combined approach was proposed that considers the role of preoperative chemoradiation, but mainly insists on the need for aggressive surgery. Just as we have known for many years now that wide surgery (tumor resection with a cuff of normal tissue all around) is a cornerstone of treatment for limb sarcomas, so too for retroperitoneal tumors every effort should be made to achieve disease-free histological margins. Of course, the situation is not the same at this particular site, because the normal tissues surrounding the tumor consist more of visceral organs than of muscle. Simple excision of the tumor mass (along with surrounding viscera only if they are already infiltrated) generally paves the way to local recurrence, so the speakers recommended an aggressive, systematic approach with en bloc multivisceral resection (e.g., the kidney, part of the colon, the diaphragm, myomectomy of the psoas, peritonectomy, vascular surgery and bone resection, depending on the tumor’s presentation); this should be carried out regardless of whether or not these surrounding tissues show macroscopic signs of infiltration, because they are generally microscopically infiltrated [17]. Such a systematic recourse to extended surgery may naturally mean a greater morbidity, but it seems to be the only approach capable of improving the dismal prognosis for patients with retroperitoneal sarcomas. Taking this view, referral to selected institutions with plenty of experience becomes a necessity. The most prominent European and North American experts were generally in favor of this approach, which is formally supported by the Soft Tissue and Bone Sarcomas Committee of the European Organisation for Research and Treatment of Cancer [102].

A whole session of the conference was dedicated to desmoid tumor (aggressive fibromatosis), and one of the main messages that emerged was that there has been a shift in the last decade from a treatment strategy based mainly on surgery to a multimodal approach. This includes various pharmacological treatments that have proved to be relatively effective, including hormone treatments (tamoxifene and toremifene), NSAIDs and IFN-α, targeted therapy such as imatinib, or ‘minimal-morbidity’ cytotoxic agents such as low-dose methotrexate combined with vinca alkaloid (vinblastine or vinorelbine) [18]. It has been demonstrated that these tumors may remain stable for a long time with or without treatment, and this has prompted the suggestion that a ‘wait-and-see’ strategy (clinical and radiological monitoring alone) may be suitable in cases of stable disease [19]. Cytogenetic studies have proved crucially important in clarifying the role of β-catenin in the genesis of desmoid tumors: a stronger nuclear expression of β-catenin would appear to predict a higher recurrence rate, and this could be used as a molecular biomarker of local recurrence and aggressive tumor biology.

A little time was also set aside for a focus on pediatric sarcomas, and specifically on rhabdomyosarcoma arising in parameningeal sites. The treatment of this high-risk tumor type poses a particular dilemma with regard to the need for new, effective, systemic therapies and novel local control methods. Ample surgical excisions are rarely (if ever) feasible without having severely mutilating effects, and radiotherapy is often burdened by major sequelae, especially in younger children. An account was given of the efforts made in pediatric oncology since the 1970s to develop research protocols and promote national and, more recently, international, multicenter cooperations. The improvements in the cure rates observed over the last 30 years (nowadays from two-thirds to three-quarters of children with rhabdomyosarcoma can be cured) are the result of these large collaborative schemes, currently being run by the Soft Tissue Sarcoma Committee of the Children’s Oncology Group and the European Pediatric Soft Tissue Sarcoma Study Group. Differences in North American and European approaches to the treatment of pediatric rhabdomyosarcoma were also illustrated at the conference, in terms of the currently used protocols and the new drugs being evaluated. On the topic of parameningeal rhabdomyosarcoma, a little time was dedicated to presenting a more specific, multidisciplinary local control strategy developed in Amsterdam (The Netherlands), called the ‘AMORE protocol’, which comprises major resection (ablative surgery), brachytherapy (moulage technique) and surgical reconstruction, performed consecutively, all within 1 week [20].

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.