Adolescent and Young Adult (AYA) Oncology, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on considerations for the comprehensive care of AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

Evaluating the Soft Tissue Sarcoma Paradigm for the Local Management of Extraskeletal Ewing Sarcoma.

OBJECTIVES: We reviewed our experience treating patients with localized extraskeletal Ewing sarcoma (EES) to determine optimal local management strategies for this rare disease. METHODS: Sixty patients with localized EES treated at our institution between 1994 and 2018 were reviewed. The Kaplan-Meier method was used to estimates disease outcomes. RESULTS: The median follow-up time was 74 months (interquartile range [IQR], 17-121). Half the patients (n = 30) received combined-modality local therapy (CMT) with both surgery and radiation therapy (RT), whereas the other half received single-modality local therapy (SMT) with either surgery or RT. All patients received chemotherapy. The 5-year overall survival was 76%. Twenty-two patients (37%) developed recurrence at a median time of 15 months (IQR, 5-56 months) resulting in 3-year progression-free survival (PFS) of 65%. On univariate analysis, the use of both neoadjuvant and adjuvant chemotherapy was associated with improved 5-year PFS (71% vs. 50%, p = .04) compared with those who received one or the other. Furthermore, 11 patients (18%) developed local recurrences at a median time of 14 months (IQR, 2-19 months), resulting in a 5-year local control (LC) rate of 77%. Use of CMT was not associated with improved LC (83% vs. 72% SMT, p = .41). Also, use of CMT was the only factor associated with poorer disease-specific survival (vs. SMT; hazard ratio, 3.4; p = .047; 95% confidence interval, 1.01-11.4). CONCLUSION: For patients with EES, CMT was not associated with a decreased rate of local relapse. These data suggest that SMT alone may be sufficient for LC in select patients. A multi-institutional collaborative effort should be considered to validate these findings. IMPLICATIONS FOR PRACTICE: Extraskeletal Ewing sarcoma is a rare chemosensitive sarcoma whose clinical course more closely follows Ewing sarcoma of bone rather than that of other soft tissue sarcomas. Based on this study, combined-modality local therapy did not confer a local control advantage compared with single-modality local therapy. Therefore, single-modality local therapy is likely adequate in select patients with favorable disease features, which has the advantage of ensuring prompt administration of systemic therapy. A multi-institutional collaborative effort is warranted to determine which patients may benefit from de-escalated local therapy.

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

Mesenchymal Chondrosarcoma: a Review with Emphasis on its Fusion-Driven Biology.

Mesenchymal chondrosarcoma is a rare but deadly form of chondrosarcoma that typically affects adolescents and young adults. While curative intent is possible for patients with localized disease, few options exist for patients in the unresectable/metastatic setting. Thus, it is imperative to understand the fusion-driven biology of this rare malignant neoplasm so as to lead to the future development of better therapeutics for this disease. This manuscript will briefly review the clinical and pathologic features of mesenchymal chondrosarcoma followed by an appraisal of existing data linked to the fusions, HEY1-NCOA2 and IRF2BP2-CDX1, and the associated downstream pathways.

Outcomes of Late-Line Systemic Treatment in GIST: Does Sequence Matter?

Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000-2021 were included. Patients were grouped by drug sequence: ripretinib-avapritinib (RA) or avapritinib-ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan-Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2-5.95) for RA and 4.73 months (1.87-15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86-18.99) for AR and 4.11 months (1.91-11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8-50.53) and 33.7 (20.03-50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing.

Retrospective evaluation of the role of gemcitabine-docetaxel in well-differentiated and dedifferentiated liposarcoma.

OBJECTIVE: Well-differentiated (WDLPS) and dedifferentiated liposarcoma (DDLPS) account for the majority of liposarcomas. Although gemcitabine-docetaxel is used as second-line treatment in soft tissue sarcomas, its efficacy in WDLPS/DDLPS is not established. This study retrospectively analyzed the efficacy of gemcitabine regimens in WDLPS/DDLPS. METHODS: All patients with WDLPS or DDLPS who received gemcitabine-based chemotherapy at our institution between September 2002 and January 2021 were included. Response was evaluated by an independent radiologist using RECIST 1.1. The Kaplan-Meier method was used to estimate distributions of survival outcomes and log-rank tests were used to compare survival outcomes between subgroups. RESULTS: Sixty-five WDLPS/DDLPS patients were included. Seven patients (10.8%) received a gemcitabine-based regimen more than once, totaling 72 treatments. The median age at the start of treatment was 66 years (range 32-80 years). Sixty-five (90.3%) regimens were gemcitabine-docetaxel, and 7 (9.7%) were gemcitabine alone. Majorities of treatments were for disease that was recurrent/metastatic (86.1%), was abdominal/retroperitoneal (83.3%), and had DDLPS components (88.9%), while 25.0% of treatments were for multifocal disease. The overall response rate was 9.7% (7/72). All responses were in patients with documented DDLPS. The median time to progression was 9.2 months (95% CI 5.3-12.3 months). The median overall survival from the start of therapy was 18.8 months (95% CI 13.1-32.4 months). CONCLUSION: Gemcitabine-docetaxel is an efficacious second-line treatment for DDLPS. Though cross study comparisons are not advisable, response to gemcitabine-docetaxel compares favorably to current standard options trabectedin and eribulin. This combination is a valid comparator arm for future second-line trials in DDLPS.

Pregnancy outcomes related to the treatment of sarcomas with anthracyclines and/or ifosfamide during pregnancy.

BACKGROUND: Sarcomas are rare diagnoses but are seen with relative frequency in adolescents and young adults and thus can present in pregnancy. We sought to study the administration of anthracyclines and/or ifosfamide in pregnancy-associated sarcomas. PATIENTS AND METHODS: We conducted a multi-institutional retrospective study, identifying sarcoma patients who received anthracyclines and/or ifosfamide during pregnancy. Chart review identified variables related to demographics, cancer diagnosis, therapies, and outcome of the patient and fetus. Wilcoxon rank-sum test compared two independent samples. RESULTS: We identified 13 patients at seven institutions with sarcoma who received anthracyclines and/or ifosfamide during pregnancy, including four bone sarcomas and nine soft tissue sarcomas diagnosed at a mean gestational age of 16.7 ± 5.9 weeks. Only nine patients had live births (9/13, 69.2%), with mean gestational age of 30.8 ± 3.8 weeks at delivery. The four patients with pregnancy loss all received both doxorubicin and ifosfamide, with chemotherapy initiated at 15.5 weeks as compared with 21.3 weeks for those patients with live births (p = 0.016). CONCLUSION: In this multi-institutional study of sarcoma chemotherapy regimens administered during pregnancy, we found a high rate of fetal demise that was seen only in patients receiving both doxorubicin and ifosfamide and statistically more likely with chemotherapy initiation earlier in the second trimester. While limited by a small sample size, our study represents the largest study of sarcoma patients that received anthracyclines and/or ifosfamide in pregnancy thus far reported and supports development of an international registry to study concerns raised by our study.

Landscape of Immune-Related Markers and Potential Therapeutic Targets in Soft Tissue Sarcoma.

Soft tissue sarcomas, depending on the subtype and grade, frequently recur and become metastatic after localized treatment. There is now great interest in applying immunotherapy to sarcomas to immuno-profile the different subtypes and immune monitor for prognosis. Our group previously showed that key immunotherapy target genes are present in sarcomas. Here, we extend our findings by demonstrating that sarcomas with a relatively high mutational load are likely to be more sensitive to immunotherapy compared to sarcomas with a lower mutation load. We also show that sarcomas with a higher mutation load are associated with the expression of key immune-related genes. We found that CD8+ T cells are present in sarcoma subtypes and that PD-L2 is highly expressed. These findings further define potential mechanisms behind the immunotherapy response of specific sarcoma subtypes and can be used to develop more optimal treatments in the future.

Impact of Lagtime, Health Insurance Type, and Income Status at Diagnosis on the Long-Term Survival of Adolescent and Young Adult Cancer Patients.

Purpose: Delays in diagnosis can affect the short-term survival outcomes of adolescent and young adult (AYA) cancer patients. We sought to determine the extent to which delayed diagnosis, health insurance type, and income status are associated with the long-term survival of AYA cancer patients. Methods: We reviewed an institutional cohort of 268 patients age 15-29 years who were diagnosed with the most common neoplasms of the AYA population between 2001 and 2003. We grouped patients by the time of onset of cancer symptomatology to verified diagnosis (lagtime to diagnosis; short or long), health insurance type at diagnosis (public or private), zip-code-based median household income (≤U.S. $50,000 or >U.S. $50,000), and demographic variables. Overall survival (OS) and late OS (LOS; the time from the 5-year anniversary of cancer diagnosis to death from any cause) were the outcomes of interest. Results: OS and LOS did not differ between those with short or long lagtimes to diagnosis for all cancer and for specific cancer types. Among patients with long lagtimes, those with private insurance had significantly better LOS than those with public insurance (p = 0.03). Compared with those who had public insurance, patients who had private insurance at diagnosis had significantly better LOS (p = 0.008). Patients with household incomes >U.S. $50,000 had better LOS than those with household incomes ≤U.S. $50,000 (p = 0.02). Patients with public insurance and household incomes ≤U.S. $50,000 had the poorest LOS. Conclusions: AYA cancer patients with either public health insurance or a low household income at diagnosis are at risk of an inferior LOS.

Transcriptional activators YAP/TAZ and AXL orchestrate dedifferentiation, cell fate, and metastasis in human osteosarcoma.

Osteosarcoma (OS) is a molecularly heterogeneous, aggressive, poorly differentiated pediatric bone cancer that frequently spreads to the lung. Relatively little is known about phenotypic and epigenetic changes that promote lung metastases. To identify key drivers of metastasis, we studied human CCH-OS-D OS cells within a previously described rat acellular lung (ACL) model that preserves the native lung architecture, extracellular matrix, and capillary network. This system identified a subset of cells-termed derived circulating tumor cells (dCTCs)-that can migrate, intravasate, and spread within a bioreactor-perfused capillary network. Remarkably, dCTCs highly expressed epithelial-to-mesenchymal transition (EMT)-associated transcription factors (EMT-TFs), such as ZEB1, TWIST, and SOX9, which suggests that they undergo cellular reprogramming toward a less differentiated state by coopting the same epigenetic machinery used by carcinomas. Since YAP/TAZ and AXL tightly regulate the fate and plasticity of normal mesenchymal cells in response to microenvironmental cues, we explored whether these proteins contributed to OS metastatic potential using an isogenic pair of human OS cell lines that differ in AXL expression. We show that AXL inhibition significantly reduced the number of MG63.2 pulmonary metastases in murine models. Collectively, we present a laboratory-based method to detect and characterize a pure population of dCTCs, which provides a unique opportunity to study how OS cell fate and differentiation contributes to metastatic potential. Though the important step of clinical validation remains, our identification of AXL, ZEB1, and TWIST upregulation raises the tantalizing prospect that EMT-TF-directed therapies might expand the arsenal of therapies used to combat advanced-stage OS.

IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers.

Background : Ten to fourteen percent of Ewing sarcoma (ES) study participants treated nationwide with IGF-1 receptor (IGF-1R)-targeted antibodies achieved tumor regression. Despite this success, low response rates and short response durations (approximately 7-weeks) have slowed the development of this therapy. Methods: We performed a meta-analysis of five phase-1b/2 ES-oriented trials that evaluated the anticancer activity of IGF-1R antibodies +/- mTOR inhibitors (mTORi). Our meta-analysis provided a head-to-head comparison of the clinical benefits of IGF-1R antibodies vs. the IGF-1R/mTOR-targeted combination. Available pretreatment clinical samples were semi-quantitatively scored using immunohistochemistry to detect proteins in the IGF-1R/PI3K/AKT/mTOR pathway linked to clinical response. Early PET/CT imaging, obtained within the first 2 weeks (median 10 days), were examined to determine if reduced FDG avidity was predictive of progression-free survival (PFS). Results: Among 56 ES patients treated at MD Anderson Cancer Center (MDACC) with IGF-1R antibodies, our analysis revealed a significant ~two-fold improvement in PFS that favored a combination of IGF-1R/mTORi therapy (1.6 vs. 3.3-months, p = 0.042). Low pIGF-1R in the pretreatment specimens was associated with treatment response. Reduced total-lesion glycolysis more accurately predicted the IGF-1R response than other previously reported radiological biomarkers. Conclusion: Synergistic drug combinations, and newly identified proteomic or radiological biomarkers of IGF-1R response, may be incorporated into future IGF-1R-related trials to improve the response rate in ES patients.

Extraskeletal Myxoid Chondrosarcomas: Combined Modality Therapy With Both Radiation and Surgery Improves Local Control.

OBJECTIVE: We evaluated our experience treating patients with localized extraskeletal myxoid chondrosarcomas (EMCs) to evaluate outcomes and relapse rates in order to better inform treatment decisions for these rare soft tissue sarcomas. MATERIALS AND METHODS: We reviewed the records of 41 consecutive patients with localized EMC treated at our institution from 1990 to 2016. Most patients (n=33, 80%) received combined modality therapy with surgery and radiation therapy, whereas only 8 (20%) underwent surgery alone. The Kaplan-Meier method was used to estimate rates of overall survival, disease-specific survival, local control (LC), and distant metastatic-free survival (DMFS). RESULTS: Median follow-up time was 94 months (range, 8 to 316). The 10-year LC, DMFS, disease-specific survival, and overall survival rates were 90%, 69%, 85%, and 66%, respectively. There were 5 patients (12%) with local relapse at a median time of 75 months (range, 13 to 176). On univariate analysis, the only significant factor associated with poorer LC was the use of surgery alone (10 y LC, 63% vs. 100% for combined modality therapy, P=0.004), which remained the only factor also significant on the multivariable analysis (P=0.02; hazard ratio [HR], 12.7; 95% confidence interval [CI], 1.4-115.3). In total, 13 patients (32%) developed distant metastatic at a median time of 28 months (range, 3 to 154). Interestingly, local recurrence was the only factor associated with poorer DMFS on multivariate analysis (P=0.04; HR, 3.9; 95% CI, 1.1-14.7). CONCLUSIONS: For patients with EMC, surgery alone was associated with a higher risk of local recurrence. Therefore, we recommend optimal local therapeutic strategies upfront with both surgery and radiation therapy to reduce the risk of local and ultimately distant recurrence.

MAGE-A3 is a Clinically Relevant Target in Undifferentiated Pleomorphic Sarcoma/Myxofibrosarcoma.

Melanoma-associated antigen 3 (MAGE-A3) expression is generally restricted to the placenta and germline cells of the testis, but it may also be expressed in sarcoma and other cancers and is associated with poor prognosis. Immunotherapy approaches targeting MAGE-A3 in other cancers have shown mixed results in the clinic, however, use of cancer testis antigens such as MAGE-A3 may have therapeutic value in the treatment of soft tissue sarcomas. Based on the recent success of anti-programmed death-1 (PD-1) therapy in undifferentiated pleomorphic sarcoma, we hypothesize that MAGE-A3-based immunotherapies may also provide benefits in this sarcoma type. We analyzed MAGE-A3 expression of sarcoma subtypes available in the Cancer Genome Atlas and Cancer Cell Line Encyclopedia and show that undifferentiated pleomorphic sarcoma/myxofibrosarcoma (UPS/MFS) expresses this potential target gene. We have identified high protein expression by tissue microarray of 106 UPS cores. We also found that high MAGE-A3 mRNA and protein expression is associated with worse overall survival in UPS/MFS. Furthermore, our results show no human leukocyte antigen (HLA) expression loss and relatively high lymphocyte infiltration by lymphocyte specific protein tyrosine kinase (LCK) marker expression. Based on these results, we propose targeting MAGE-A3 in UPS/MFS by immunotherapy techniques.

Emergency Department Visits by Adolescent and Young Adult Cancer Patients Compared with Pediatric Cancer Patients in the United States.

PURPOSE: Limited information exists on emergency department (ED) visits for adolescent and young adult (AYA) patients with cancer. We examined the clinical reasons for ED visits, and outcomes, for AYAs with cancer compared to pediatric cancer patients. METHODS: The 2013 Nationwide Emergency Department Sample data were used to identify 53,274 AYA (ages 15-39) and 6952 pediatric (ages 0-14) cancer ED visits. We evaluated patient (i.e., demographic and diagnosis) and hospital characteristics, and the ED event outcome (admitted to the same hospital or treated/released). Clinical reasons for visits were identified as procedures, infections, or noninfectious toxicities. Variables were compared between groups using chi-squared tests. Logistic regressions identified characteristics associated with the outcome between and within groups. RESULTS: AYA cancer visits were more likely to be self-paid (15.8% vs. 1.9%, p < 0.001), and be from low-income households and nonmetro counties than pediatric visits. Toxicity was the most prevalent reason for AYA visits (46.0%) and infections for pediatrics (47.3%, p < 0.001). AYA cancer visits were less likely to be admitted (OR = 0.84, 95% CI = 0.71-0.98; p = 0.03) than pediatric cancer. Among AYAs, self-paid visits were less likely to be admitted compared with privately insured visits (OR = 0.58, 95% CI: 0.52-0.66, p < 0.001). Self-pay did not affect the outcome for pediatric visits. CONCLUSIONS: In the United States, compared with pediatric cancer patients, AYAs with cancer visit EDs more often for toxicity-related problems, and are more often self-paid and from poorer households. These distinctive features impacting health service use should be incorporated into care plans aimed at delineating effective care for these patients.

Overexpressed PRAME is a potential immunotherapy target in sarcoma subtypes.

BACKGROUND: PRAME (preferentially expressed antigen in melanoma), a member of the cancer-testis antigen family, has been shown to have increased expression in solid tumors, including sarcoma, and PRAME-specific therapies are currently in development for other cancers such as melanoma. METHODS: To map the landscape of PRAME expression in sarcoma, we used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) projects and determined which sarcoma subtypes and subsets are associated with increased PRAME expression. We also analyzed how PRAME expression correlates with survival and expression of markers related to antigen presentation and T cell function. Furthermore, tumor and normal tissue expression comparisons were performed using data from the genotype-tissue expression (GTEx) project. RESULTS: We found that uterine carcinosarcoma highly overexpresses the PRAME antigen, and synovial sarcomas and multifocal leiomyosarcomas also show high expressions suggesting that PRAME may be an effective target of immunotherapies of these tumors. However, we also discovered that PRAME expression negatively correlates with genes involved in antigen presentation, and in synovial sarcoma MHC class I antigen presentation deficiencies are also present, potentially limiting the efficacy of immunotherapies of this malignancy. CONCLUSIONS: We determined that uterine carcinosarcoma, synovial sarcoma, and leiomyosarcoma patients would potentially benefit from PRAME-specific immunotherapies. Tumor escape through loss of antigen presentation needs to be further studied.