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Differentiated thyroid cancer (DTC) affects thousands of lives worldwide every year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) the quality of life and might be unnecessary in indolent DTC cases. This clinical setting highlights the unmet need for a precise molecular diagnosis of DTC, which should dictate appropriate therapy. Here we propose a differential multi-omics model approach to distinguish normal gland from thyroid tumor and to indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. Based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intratumor heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. Specifically, normal and tumor thyroid tissues from these patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumor cells. Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. Well-designed, prospective translational clinical trials will ultimately show the value of this targeted molecular approach.TRANSLATIONAL RELEVANCEIn this article, we propose a new integrated metabolic, genomic, and cytopathologic methods to diagnose Differentiated Thyroid Cancer when the conventional methods failed. Moreover, we suggest metabolic and genomic markers to help predict high-risk Papillary Thyroid Cancer. Both might be important tools to avoid unnecessary surgery and/or radioiodine therapy that can worsen the quality of life of the patients more than living with an indolent Thyroid nodule.Graphical Abstract

Background: The addition of neoadjuvant platinums to standard chemotherapy regimens for triple negative breast cancer (TNBC) improves rates of pathologic complete response (pCR). Our prior trial combining carboplatin (CAR) with liposomal doxorubicin (DOX) for metastatic TNBC showed good response rates with minimal side effects and allows for higher platinum dosing. We hypothesized that the doublet of DOX+CAR is effective and tolerable in the neoadjuvant setting for TNBC and tumor genomics may identify biomarkers of complete response and actionable targets. Methods: A phase II single arm trial was conducted for patients (pts) diagnosed with stage II-III TNBC. Patients received 4 cycles of neoadjuvant carboplatin (AUC 5) and liposomal doxorubicin (30mg/m2) administered every 28 days, then underwent definitive breast surgery followed by 12 weeks of adjuvant paclitaxel 80 mg/m2 administered weekly. Primary and secondary clinical endpoints were rate of pCR and two year recurrence free survival (RFS) and overall survival (OS), respectively. Cardiac safety of the combination was assessed. Fresh residual tumor samples were obtained at time of surgery for generation of patient derived xenografts (PDX). Whole genome sequencing (WGS) and RNA sequencing will be performed to evaluate specific patterns of small-variant mutations and patterns of structural variants to identify which patients are likely to have pCR. Results: From 2/2015 to 6/2021, 62 pts were enrolled, 8 pts withdrew consent either prior to treatment or completion of neoadjuvant therapy and/or surgery. Median age of the cohort was 55.4 years. There was high participation by under-represented groups: 17.0% African American, 20.8% Asian, 13.2% Hispanic. Most histologies were invasive ductal carcinoma, but included apocrine, pleomorphic lobular, and metaplastic subtypes. 53 pts completed all 4 cycles of neoadjuvant DOX+CAR, followed by definitive surgery; 1 pt progressed after 1 cycle and proceeded to surgery thereafter. 30.2% (16) pts achieved pCR, and residual cancer burden (RCB) will be reported in patients with residual disease. Of the 53 pts who completed 4 cycles of treatment, 5 pts progressed (recurrence or death) within two years from time of surgery (4 distant and 1 local recurrence), yielding the 2-year recurrence-free-survival rate of 90.3% (95%CI 81.0%, 99.6%). The most common toxicities during DOX+CAR were grade 1 fatigue in 50 pts (92.6%), grade 1 anemia in 44 pts (81.5%), and grade 3/4 neutropenia in 16 pts (29.6%); these pts received GCSF support with subsequent cycles; febrile neutropenia occurred in 1 pt (1.9%) in this group. Only 10 pts (18.5%) had grade 1 alopecia, 5 pts (9.3%) had grade 2 alopecia, 2 pts (3.7%) had grade 3 thrombocytopenia. There were no delays in treatment due to cardiotoxicity or complications from surgical healing. Of the 37 pts who had residual disease, PDX was attempted in 21 pts, and 16 (76%) PDX were established, including those for 4 patients experiencing recurrence. WGS and RNA sequencing data from pre-treatment and residual disease samples will be analyzed and reported.Conclusion: 4 cycles of neoadjuvant DOX+CAR achieved rate of pCR similar to standard regimens and has good tolerability. Post chemotherapy PDX is feasible and may help identify targeted approaches for patients with resistant disease. These results warrant further evaluation of this combination for early stage TNBC. Citation Format: Nancy Chan, Shou-en Lu, Yue Wang, Gregory M Riedlinger, Coral Omene, Mridula George, Jyoti Malhotra, Maria Kowzun, Firas G Eladoumikdachi, Lindsay B Potdevin, Shicha Kumar, Kant Matsuda, Shruti Desai, Nayana Patel, Deborah L Toppmeyer, Shridar Ganesan, Kim Hirshfield. Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of early stage triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-15.

Background:Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.Methods:We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel.Results:These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status.Conclusions:Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.Funding:R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.Clinical trial number:NCT03941782

BackgroundLymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.MethodsWe examined the genomic landscape of a patient cohort of LMs (n=30 cases) that underwent comprehensive genomic profiling (CGP) using a large-panel next generation sequencing (NGS) assay. Immunohistochemical analyses were completed in parallel.ResultsThese LMs had low mutational burden with hotspot PIK3CA mutations and NRAS mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal lymphatic malformation harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable complete response to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive in vitro to alpelisib in a concentration-dependent manner.ConclusionsOur findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.FundingR.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.Clinical trial numberNCT03941782

Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.We examined the genomic landscape of a patient cohort of LMs (These LMs had low mutational burden with hotspotOur findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.NCT03941782.

Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1–9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1–E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.

FGFR-TACC fusions, including FGFR3-TACC3, have been identified as potential oncogenic drivers and actionable alterations in a number of different cancer types. The clinical relevance of FGFR3-TACC3 fusions in endometrial cancer has not yet been described. Formalin-fixed, paraffin-embedded metastatic endometrial carcinoma from the spleen and peritoneum were sent for comprehensive genomic profiling (CGP) using the FoundationOne platform as part of a prospective tumor genomic profiling protocol. We report the identification of an FGFR3-TACC3 fusion in a case of metastatic endometrioid endometrial cancer. Other potentially actionable alterations detected in this specimen included PIK3CA T1025S and an uncharacterized rearrangement involving TSC2. The patient initially received an FGFR inhibitor as an investigational agent and experienced stable disease with complete resolution of a pelvic nodule; however, treatment had to be discontinued because of intolerable side effects. A PET/CT scan nearly 3 mo after discontinuation showed disease progression. She subsequently received the mTOR inhibitor, temsirolimus, later accompanied by letrozole, and achieved stable disease. Clinical benefit was attributed to the mTOR inhibitor as tumor stained negative for estrogen receptor. Temsirolimus was discontinued after >17 mo because of disease progression. FGFR inhibitors may have clinical benefit in the treatment of endometrial carcinoma with FGFR3-TACC3 fusions. Additionally, clinical benefit from an mTOR inhibitor may reflect a response to targeting the alteration in PIK3CA or TSC2. More research is needed to understand the activity of FGFR3-TACC3 fusions on tumors and to discover additional therapeutic options for endometrial carcinoma patients with this gene fusion.