Chaitali Singh Nangia

Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial

BACKGROUND Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer. METHODS This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093. FINDINGS Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently reported grade 3 and 4 adverse events in the safety set were hyperglycaemia (seven [8%] of 92 patients), rash (four [4%]), and dyspnoea (three [3%]). Serious adverse events were reported in 20 (22%) patients; six (7%) were deemed treatment related, with dyspnoea (three [3%]) and pneumonia (two [2%]) reported most frequently. 12 (13%) of 92 patients had adverse events suspected to be related to treatment that led to discontinuation of everolimus and exemestane (the most common were rash, hyperglycaemia, and stomatitis, which each affected two [2%] patients). INTERPRETATION Prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy. FUNDING Novartis Pharmaceuticals Corporation.

Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma

Objective: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. Methods: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. Results:RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. Conclusions: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

Prevention of everolimus/exemestane (EVE/EXE) stomatitis in postmenopausal (PM) women with hormone receptor-positive (HR+) metastatic breast cancer (MBC) using a dexamethasone-based mouthwash (MW): Results of the SWISH trial.

189 Background: Stomatitis is a frequent adverse event (AE) associated with mTOR inhibition. In BOLERO-2 patients (pts) receiving EVE/EXE, all grade (Gr) stomatitis was 67%; 33% had Gr ≥ 2 and 8% Gr 3. Median time to ≥ Gr 2 onset was 15.5 days; incidence of new stomatitis (Gr ≥ 2) plateaued at 6 wks. In a meta-analysis, 89% of first stomatitis events occurred within 8 wks. Topical steroids are used to treat aphthous ulcers; anecdotal use as prophylaxis has been reported. METHODS Eligibility included PM women with HR+ MBC prescribed EVE/EXE. Treatment included EVE 10 mg and EXE 25 mg QD, with 10 mL of commercially available 0.5 mg/5 mL dexamethasone oral solution to swish x 2 min and spit QID for 8 wks starting day 1. Pts completed a daily adherence log, including an oral pain (range 0-10) and normalcy of diet score. The primary endpoint was to compare the incidence of Gr ≥ 2 stomatitis at 8 wks with BOLERO-2 results. Secondary endpoints included MW use by average times/day, EVE/EXE dose intensity, incidence of all Gr stomatitis and time to resolution to Gr ≤ 1. RESULTS 92 women were enrolled; 86 were evaluable for efficacy. Median age was 61 yrs (range 34-87); median dose intensity was 10 (range 3-10) and 25 mg (range 8-25) for EVE and EXE, respectively. 95% of pts used the MW 3-4 times/day (median MW use/day = 3.95, range 1.9-4). At 8 wks, the rate of ≥ Gr 2 stomatitis was 2.4% (2 pts) with a Gr 1 rate of 18.8%. A comparison of stomatitis incidence by grade between BOLERO-2 and SWISH is shown in the table. In the 75 patients with complete ECOG scores, 88% maintained/improved ECOG status. Mean pain scale score was < 1 at all visits; 88% of pts reported a normal diet at 8 wks. 13% discontinued EVE/EXE due to suspected related AEs (most common: rash, 2%; hyperglycemia, 2%; stomatitis, 2%; and pneumonitis, 1%). CONCLUSIONS Prophylactic use of 0.5 mg/5 mL dexamethasone oral solution markedly decreases the incidence and severity of stomatitis in patients receiving EVE/EXE for MBC and should be considered a new standard of oral care in this setting. CLINICAL TRIAL INFORMATION NCT02069093. [Table: see text].

Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options

BACKGROUND Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. MATERIALS AND METHODS We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). RESULTS Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA, NF1, CDKN2A, and CDKN2C occurring in 7% of samples. CONCLUSION We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. IMPLICATIONS FOR PRACTICE Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), and alterations in PIK3CA, NF1, CDKN2A, or CDKN2C were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics.

Pancytopenia in a patient with cystinosis secondary to myelosuppression from cystine crystal deposition: a case report

IntroductionCystinosis is a rare metabolic genetic disorder caused by a mutation in the cystinosin lysosomal cystine transporter gene. Clinically, it is characterized by systemic accumulation of cystine crystals in tissues causing end-organ dysfunction in the kidney, eyes, muscles, and other organs in the body. In very rare cases, it can also involve the bone marrow and the resulting cystine crystal deposition can cause myelosuppression leading to pancytopenia.Case presentationHere we report the case of a 26-year-old white woman with cystinosis and other complex medical comorbidities who developed pancytopenia. She was worked up extensively and ruled out for common causes of pancytopenia (infectious disorders, vitamin deficiencies secondary to gastrointestinal malabsorption, rheumatologic, and hematologic disorders). On bone marrow biopsy she was found to have extensive deposits of cystine crystals, which was thought to be the cause of her myelosuppression leading to her pancytopenia. As a result, by treating her underlying cystinosis more aggressively we were able to observe an improvement in her pancytopenia a few months afterwards.ConclusionsPancytopenia secondary to myelosuppression from cystine crystal deposition in the bone marrow is a very rare complication that has been reported in only a handful of case reports. This case illustrates the importance of keeping a broad differential diagnosis and systematically ruling out common causes of pancytopenia. It also demonstrates the importance of bone marrow biopsies in the evaluation of unexplained pancytopenia.

Composite liver tumors: a radiologic-pathologic correlation

Bi-phenotypic neoplasm refers to tumors derived from a common cancer stem cell with unique capability to differentiate histologically into two distinct tumor types. Bi-phenotypic hepatocellular carcinoma-cholangiocarcinoma (HCC-CC), although a rare tumor, is important for clinicians to recognize, since treatment options targeting both elements of the tumor are crucial. Imaging findings of bi-phenotypic HCC-CC are not specific and include features of both HCC and CC. A combination of imaging and immuno-histochemical analysis is usually needed to make the diagnosis.

Contents Vol. 90, 2016

A.B. Benson, Chicago, Ill. A. Chang, Singapore A.L. Cheng, Taipei J.F. Cleary, Madison, Wis. M. Dietel, Berlin M.S. Ernstoff, Cleveland, Ohio M.G. Fakih, Duarte, Calif. J.J. Grau, Barcelona H. Gronemeyer, Illkirch D.F. Hayes, Ann Arbor, Mich. C.S. Johnson, Buffalo, N.Y. M.J. Kelley, Durham, N.C. L. Kumar, New Delhi P.J. Loehrer, Indianapolis, Ind. J.R. Marshall, Buffalo, N.Y. S. Monfardini, Milan R. Nagler, Haifa R. Ohno, Nagoya B. Pestalozzi, Zurich H.M. Pinedo, Amsterdam E.A. Repasky, Buffalo, N.Y. A. Semczuk, Lublin E.F. Smit, Amsterdam C.N. Sternberg, Rome R. Stupp, Zurich M.S. Tallman, New York, N.Y. S. Tanaka, Hiroshima M. Tian, Houston, Tex. D.L. Trump, Buffalo, N.Y. T. Wiegel, Ulm W. Yasui, Hiroshima H. Zhang, Hangzhou City Editor-in-Chief