Highlights From a Year With Significant Advances in Sarcoma Therapy and Related Progress in Detecting Recurrences, Mutational Subtypes of GIST

A recap of new information presented in the GIST and Sarcoma Journal suggests trends to follow in ongoing and future clinical trials. The information in this section represents summaries of the full articles published during the year. The complete articles can be viewed on the GIST and Sarcoma website— http://www.gistsarcomajournal.com

Imaging to Detect Recurrent GIST After Surgery:
Controversies, Consensus and Guidelines
New recently published information, much of it based on expert consensus opinion and guidelines, is removing much of the uncertainty surrounding the optimal approach to detect recurrent gastrointestinal stromal tumor (GIST).  Although patients with GIST are generally followed up after surgery with longitudinally repeated imaging examinations to maximize the earliest detection of recurrence, there have been relatively few definitive studies on followup, the optimal approach for doing so may be unknown to many clinicians, and there has been a wide variation in guidelines.

All of this is changing rapidly with new reports clarifying our options, according to Wilbur B. Bowne, MD, Associate Professor of Surgery at Drexel University, Philadelphia. Until recently, however, there was a gap in the literature regarding optimal strategies because prospective studies were not conducted to investigate different follow-up schedules and methods. Key evidence is emerging on the rationale from groups like the National Comprehensive Cancer Network and the European Society for Clinical Oncology; additional expert opinions are available from consensus reports from other groups who have studied surveillance in high risk groups.  All of this information is building on a solid framework consisting of well recognized prognostic factors to help guide decision making.

Numerous reports have delineated the factors involved. The most important prognostic factor for recurrence is tumor proliferation rate, often assessed by counting of the number of mitotic figures per 50 high power fields (HPFs) of the microscope or by providing the number of mitotic figures per 1 mm2 of tumor. There are also other factors that are often independently associated with a high risk of recurrence, including non-gastric location of GIST, large size and tumor rupture.

Population-Based Study Provides Insight into GIST
Epidemiology and Risk of Additional Cancers
Although we have not completely deciphered the epidemiology of gastrointestinal stromal tumor (GIST) and additional cancers, a new population based study uses modern data collection resources to sort out significant temporal and disease associations between GIST and other cancers. Expanding upon the publications from several single institution studies, Jason Sicklick, MD and colleagues broadened the data set and cast a wider net to build upon these important earlier studies. Dr Sicklick is Assistant Professor of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, UC San Diego Health System.

Until recently, we relied upon the results of several descriptive, single-institution case series to determine the likelihood that patients with sporadic GISTs develop synchronous or metachronous malignancies. These studies qualitatively characterized cancer associations, but the findings were unsatisfying in their variability. For example, in a review by Agaimy and colleagues that included 4,813 patients, the frequency of additional malignancies varied from 4.5% to 33% in patients with GIST. There have been other large studies that added to this body of literature. For example, single or multiple institution studies have dem-onstrated associations between GIST and desmoids, acute myeloid leukemia, and other gastrointestinal malignancies found incidentally. While a hereditary etiology has been attributed to approximately 5% of all GIST cases associated with multiple benign and malignant tumors, Sicklick et al attempted to quantify the frequency and temporal relationships of GIST to other cancer histologies in the remaining 95% of GIST patients without known hereditary GIST syndromes. These single-institution studies were helpful but they did not provide the broad-based characterizations.

In his Editorial in the journal, Cancer, Dr Constantine Stratakis, Scientific Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, wrote that it is a “different world out there for clinical oncology, one that changes every day because of the availability of large patient cohorts and the advances of modern genetics.” Population-based studies take advantage of the growing repository of data to make new associations, draw novel conclusions and possibly shift thinking about the histology and mechanics of diseases like GIST. In our recently published study, Sicklick et al utilized population-level data in the United States in order to define demographic, clinical characteristics, and temporal factors associated with increased probability of developing additional malignancies. From data culled from the Surveillance, Epidemiology, and End Results (SEER) database, the authors identified further evidence supporting the existence of nonrandom associations between GIST and other malignancies. This report builds on the foundation created by these studies with the hypothesis that greater insight could be gained into possible associations between GIST and other primary tumors with a national cancer database inquiry. Aside from the impact the findings may have on understanding GIST from a purely epidemiological perspective, the associations have important clinical implications for future cancer screening and treatment strategies.

Key Findings
The key findings emerging from this study include the following:

  • One-in-5.8 patients with GIST will develop additional malignancies before and after their diagnosis.
  • When compared to the United States population, people with GIST had a 44% increased prevalence of cancers occurring before a GIST diagnosis and a 66% higher incidence of developing cancers after diagnosis.
  • Patients with GIST are more likely to develop many cancers, including other sarcomas, non-Hodgkin’s lymphoma, carcinoid tumors, melanoma, colorectal, esophageal, pancreatic, hepatobiliary, non-small cell lung, prostate and renal cell cancers.
  • Non-Hispanic patients had a higher incidence of other cancers before a GIST diagnosis.
  • Patients with tumors smaller than 10 cm had a higher probability of a second cancer than patients with larger tumors.
  • Patients with tumors smaller than 2 cm had the greatest likelihood of developing additional malignancies, both before and after diagnosis.
  • Patients diagnosed with GIST may warrant consideration for additional screenings based on the other cancers that they are most susceptible to develop.

Hereditary GIST: A Growing Awareness of
Mutational Subtypes Is Redefining Recommendations
for Familial Screening, Surveillance
KIT and PDGFRA  generally represent the molecular hallmark of GIST. But the recent identification of other molecular characteristics beyond KIT and PDGFRA are driving a new view of the disease. Identification of germline mutations underscores the need for patients with these familial risk factors to undergo genetic counseling to determine appropriate followup and management. As new reports elucidate distinctions between subtypes of hereditary GIST, we are discovering how these mutations of GIST differ clinically, pathologically, and behaviorally from sporadic gastric tumors, according to Joshua D. Schiffman, MD, Professor,  Department of Pediatrics and Adjunct Professor, Department of Oncological Sciences, School of Medicine at the University of Utah, Salt Lake City.

Deeper insights into the biology of gastrointestinal stromal tumors (GISTs) are reshaping perceptions about GIST, its genetic risk factors and a diverse set of mutations and genotype features with clinical implications. Although GIST typically affects patients over the age of 40 years, recognition of its epidemiology in children and young adults has been increasingly recognized even though these younger groups account for only 1.4% of patients with the tumor.

  • Though the majority of GISTs appear to arise sporadically, a number of families with high frequencies of GISTs have been reported and germline mutations have been identified. The true frequency of all GIST diagnoses has been difficult to determine because the definition of GIST was derived in 1990 before it was molecularly characterized. One United States report from the Surveillance, Epidemiology, and End Results (SEER) database indicated that, from 1992 to 2000, the yearly incidence rate in the United States was 6.8 cases per million.
  • Most GISTs occurring in adults are driven by activating mutations in the KIT or PDGFRA genes. New findings on molecular classification, however, have dramatically changed the nomenclature for various GISTs and contributed to an improved understanding of hereditary and familial factors. For example, 85% of GISTs in children and 10% to 15% of GISTs in adults are negative for KIT and PDGFRA mutations and are commonly referred to as wild-type (WT) GIST. Because these malignant neoplasms are rare, efforts to delineate their natural history and determine their response to treatment have been difficult. This is particularly true with regard to the use of kinase inhibitor therapies: WT GIST generally does not respond to tyrosine kinase therapy known to be effective in non-WT GIST. From institutional series and case reports WT GIST has been characterized as primarily affecting young females, multifocal and primarily having a gastric location.

The Trabectedin Story: How a New Combination
Is Shifting the Paradigm of Treatment in Advanced
Uterine Leiomyosarcoma (uLMS)
Novel strategies are needed for the treatment of advanced uterine leiomyosarcoma. Until recently, this has largely been an elusive goal given the well-recognized and daunting limitations of conventional chemotherapeutic regimens. Robust evidence from recent studies, however, suggests how a new combination is changing perspectives on this disease, offering improved insights into the tumor microenvironment and delineating mechanisms of action, according to Marilyn Huang, MD, MS, Assistant Professor Division of Gynecologic Oncology, University of Miami/ Sylvester Comprehensive Cancer Center, Miami, Florida.

Moderate chemosensitivity and propensity for recurrence despite early stage portending an overall poor prognosis are perhaps the hallmarks to describe the challenges underlying treatment considerations in metastatic u-LMS. The cornerstone of treatment remains surgical resection. Following surgery, cytotoxic chemotherapy is often considered due to risk of recurrence. Chemotherapy is commonly doxorubicin or combination therapy with gemcitabine and docetaxel, although other chemotherapeutic agents such as dacarbazine and ifosamide have also been investigated. Multiple studies have demonstrated the challenges of treatment: estimated median survival remains 12 to 15 months for u-LMS.

Uterine sarcomas comprise approximately 3-7% of all uterine malignant neoplasms, of which u-LMS are the most common. Unfortunately, regardless of stage, u-LMS signifies a poor prognosis with few viable chemotherapy options. There are challenges in the diagnosis of u-LMS compared to other uterine cancers. In the case of endometrial cancer, the tumor originates from the endometrial lining, causing early bleeding in its development in >90% of women. Sampling of the endometrium yields malignant cells and an early diagnosis is typically achieved. However, endometrial sampling for early u-LMS may not be diagnostic and is often not performed by gynecologists in the setting of suspected uterine leiomyomas. Frequently, uLMS is not diagnosed until postoperatively at time of pathology review. Furthermore, u-LMS has a high propensity for both direct invasion as well as hematogenous spread and is relatively chemoinsensitive, making the disease difficult to treat. Optimal management of u-LMS is challenging and typically involves a multidisciplinary team whose approach generally depends on the disease spread (ie, localized vs disseminated disease).

Novel Combination—Olaratumab + Doxorubicin—
Suggests Potential Paradigm Shift in Treatment
of Soft-Tissue Sarcoma
The elusive goal of a therapy producing a pronounced survival benefit along with an acceptable safety profile in advanced soft-tissue sarcoma may be within reach. Not with chemotherapeutic approaches per se, but by combining a monoclonal antibody with doxorubicin. A new fully accrued trial is building on evidence pointing toward inhibition of a more clearly defined signaling pathway, based on a report by Gary K. Schwartz, MD, Chief, Division of Hematology and Oncology, Columbia University Medical Center, New York.

If a phase 3 clinical trial now underway can confirm or even improve upon the results achieved in earlier phases with a novel drug combination, a pronounced overall survival benefit may soon be available for patients with metastatic soft-tissue sarcoma. The development of novel systemic treatments in soft-tissue sarcomas is challenging; there are more than 70 different histological subtypes, and these subtypes show a heterogeneous genetic composition and clinical behavior. Within the subtypes there are also differences in overall survival as measured from the start of the first systemic treatment for advanced disease.

Given the little progress in improvement of median overall survival in patients with advanced soft-tissue sarcoma, the positive findings from an open-label phase 1b and randomized phase 2 trial suggest a potential shift in the paradigm for treatment. The study by Tap et al is believed to be the first randomized study to show increased survival for patients with soft-tissue sarcoma treated with a drug added to the standard-of-care doxorubicin treatment over single-agent doxorubicin. Among the key findings:

  • A combination of olaratumab plus doxorubicxin improved both progression-free survival (PFS) and overall survival compared with doxorubicin only.
  • The improvement of 11.8 months in median overall survival is highly significant, a difference of 80% compared with doxorubicin alone. The improvement in PFS was 2.5 months, a 61% advantage over doxorubicin alone.

Results from this investigation and, potentially data from the ongoing phase 3 trial now fully accrued, highlight the importance of a signaling pathway in the biology of soft-tissue sarcomas and how this pathway may be inhibited by the use of olaratumab, a monoclonal antibody. Platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) signaling plays a significant part in mesenchymal biology, including mesenchymal stem cell differentiation, growth, and angiogenesis.There is additional evidence from other reports on its importance: this pathway is also involved in cancer through aberrant cellular signaling. More specifically, it is believed to play a role in modulating the tumor or stromal microenvironment and facilitating metastases in several malignancies.

If these postulates are correct, then orlaratumab could have a significant impact on altering the course of soft-tissue sarcoma. Olaratumab is a recombinant human immunoglobulin G subclass (IgG1) monoclonal antibody that binds PDGFRα, blocking PDGF-AA, PDGF-BB and PDGF-CC binding and receptor activation.  Preclinical experience with olaratumab alone or in combination with doxorubicin—with results derived from human sarcoma xenograft models—suggested antitumor activity.  GSJ



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