Lara Dunn

Predictors of Outcome in Adenoid Cystic Carcinoma of Salivary Glands: A Clinicopathologic Study With Correlation Between MYB Fusion and Protein Expression

Adenoid cystic carcinoma (ACC) is the second most common salivary gland malignancy and it has a high rate of recurrences and a poor long-term prognosis. Our aim was to assess the prognostic factors in ACC and study MYB-NFIB fusion and MYB protein expression in a large retrospective cohort of 135 patients with a median follow-up of 6.3 years. The 5- and 10-year local recurrence-free survival (RFS) rate of 94% and 78%, 5- and 10-year distant metastasis survival rate of 77% and 58%, and 5- and 10-year RFS of 66% and 44%. The following features were identified as adverse prognostic factors of RFS on univariate analysis: large tumor size, solid growth pattern, increased mitoses, positive margin, American Joint Committee on Cancer clinical staging, high-grade transformation, vascular invasion, nuclear atypia, open chromatin, prominent nucleoli, and tumor necrosis. However, on multivariate analysis, only increased mitoses (≥5/10 high-power fields), any solid growth pattern, and advanced American Joint Committee on Cancer TNM staging were independent adverse predictors for RFS. MYB immunoexpression and MYB-NFIB translocation were common findings in ACC, occurring in 72% and 59% of the tested ACCs, respectively. The sensitivity and specificity of MYB immunohistochemistry in detecting MYB-NFIB fusion was relatively low at 78% sensitivity and 50% specificity. The high prevalence of alterations leading to high expression of the MYB transcription factor family suggests that targeted approaches developed to suppress the expression of these oncogenic transcription factors and/or the transcriptional activity of these proteins would be a rational therapeutic approach to investigate in ACC.

Patterns of Treatment Failure and Postrecurrence Outcomes Among Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma After Chemoradiotherapy Using Modern Radiation Techniques

Importance Even though 15% to 50% of patients with head and neck squamous cell carcinoma (HNSCC) experience recurrence, relatively little is known regarding patterns of treatment failure and postrecurrence outcomes after chemoradiotherapy using modern radiation techniques (intensity-modulated radiotherapy [IMRT]). Recurrence patterns are significantly affected by variations in the quality of radiotherapy, which may confound findings from multicenter trials. Objective To assess patterns of treatment failure and postrecurrence outcomes for patients with HNSCC treated with contemporary radiotherapy techniques. Design, Setting, and Participants This large single-institution cohort study reviewed the outcomes of 1000 consecutive patients with stage III to IVB oropharyngeal carcinoma (n = 703), laryngeal carcinoma (n = 126), or hypopharyngeal carcinoma (n = 46) treated with definitive IMRT with or without concurrent chemotherapy, as well as patients with oral cavity carcinoma (n = 125) treated with postoperative IMRT with or without concurrent systemic therapy, from December 1, 2001, to December 31, 2013, with a median follow-up of 65.1 months among surviving patients. Data analysis was performed from January 31, 2016, to February 17, 2017. Main Outcomes and Measures Patterns of treatment failure and overall survival following locoregional failure or distant metastasis. Results Among the 1000 patients (186 women and 814 men; mean [SD] age, 59.3 [10.8] years), there were no marginal or isolated out-of-radiation-field failures. Among subsites, the cumulative incidence of local failure was highest among patients with oral cavity carcinoma vs those with oropharyngeal carcinoma (hazard ratio, 5.2; 95% CI, 3.1-8.6; P < .001). Furthermore, patients with oral cavity carcinoma experienced significantly shorter survival following distant metastasis (hazard ratio, 3.66; 95% CI, 1.98-6.80; P < .001). Patients with oropharyngeal carcinoma positive for human papillomavirus or p16 lived longer after locoregional failure compared with patents with oropharyngeal carcinoma negative for human papillomavirus or p16 (median survival, 36.5 vs 13.6 months; P = .007) but not after distant metastasis. Salvage surgery was associated with improved overall survival following locoregional failure (hazard ratio, 0.51; 95% CI, 0.34-0.77; P = .001); oligometastatic disease (1 vs ≥2 lesions: hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001) was associated with improved overall survival following distant metastasis. Conclusions and Relevance Overall survival after recurrence of HNSCC is influenced by the HNSCC subsite and human papillomavirus or p16 status, as well surgical and systemic interventions. An oligometastatic phenotype characterizes patients with solitary metastasis after chemoradiotherapy. These findings have important implications for clinical trial designs for HNSCC in the recurrent and oligometastatic setting.

Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer

Patients with recurrent and/or metastatic, radioactive iodine‐refractory thyroid carcinoma have limited treatment options. Sorafenib, an oral kinase inhibitor, is approved by the US Food and Drug Administration for the treatment of radioactive iodine‐refractory thyroid carcinoma, although it demonstrated low response rates (12.2%) as a single agent in the first‐line setting. The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results.

Therapy: Lenvatinib and radioiodine-refractory thyroid cancers

Over the past decade, several multikinase inhibitors have shown considerable effectiveness against metastatic radioiodine-refractory thyroid cancers in early stage clinical trials. On the basis of some remarkable results in a phase III clinical trial, lenvatinib now joins sorafenib as another multikinase inhibitor approved by the FDA for this disease.

PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma

Background No systemic therapies have been approved for the treatment of advanced cutaneous squamous‐cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose‐escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous‐cell carcinoma. Methods We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous‐cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic‐disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review. Results In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic‐disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow‐up was 7.9 months in the metastatic‐disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic‐disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event. Conclusions Among patients with advanced cutaneous squamous‐cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498.)

Phase I study of induction chemotherapy with afatinib, ribavirin, and weekly carboplatin and paclitaxel for stage IVA/IVB human papillomavirus-associated oropharyngeal squamous cell cancer

The human papillomavirus (HPV) E6 oncoprotein enhances the oncogenic potential of ErbB proteins in HPV‐related malignancies. This phase I study evaluates the addition of afatinib, an ErbB family inhibitor, and ribavirin to paclitaxel and carboplatin induction chemotherapy in HPV‐associated, locally advanced oropharyngeal squamous cell carcinoma (SCC).

Lenvatinib and radioiodine-refractory thyroid cancers

Over the past decade, several multikinase inhibitors have shown considerable effectiveness against metastatic radioiodine-refractory thyroid cancers in early stage clinical trials. On the basis of some remarkable results in a phase III clinical trial, lenvatinib now joins sorafenib as another multikinase inhibitor approved by the FDA for this disease.

Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers

CONTEXT BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). OBJECTIVES To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). DESIGN This was a pilot trial that enrolled from June 2014 to January 2016. SETTING Academic cancer center. PATIENTS Patients with RAIR, BRAF mutant thyroid cancer. INTERVENTION Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. MAIN OUTCOME MEASURE The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. RESULTS Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). CONCLUSIONS Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.

Lenvatinib and radioiodine-refractory thyroid cancers: Therapy

Over the past decade, several multikinase inhibitors have shown considerable effectiveness against metastatic radioiodine-refractory thyroid cancers in early stage clinical trials. On the basis of some remarkable results in a phase III clinical trial, lenvatinib now joins sorafenib as another multikinase inhibitor approved by the FDA for this disease.

Abstract P2-12-05: Limited Absorption of Low Dose 10µg Intravaginal 17-β Estradiol (Vagifem®) in Postmenopausal Women with Breast Cancer on Aromatase Inhibitors

Background: Aromatase inhibitors (AIs) are used to treat postmenopausal women with hormone-receptor positive (HR+) breast cancer (BC). AIs block the peripheral conversion of androgens to estrogen (E), resulting in sub-physiologic levels of E that may lead to profound urogenital atrophy. Atrophic vaginitis in BC survivors is prevalent and its management is complex. An observational study (n = 6) demonstrated elevated estradiol levels in 5/6 women on AIs after 2 weeks (wks) of treatment with 25µg 17-β Estradiol (Vagifem ®), which raised questions regarding the safety of intravaginal estradiol in women with HR+ BC. However, the small sample size limited definitive conclusions, yet underscored the need for a clinical trial to evaluate concurrent use of AIs and intravaginal estradiol. In addition, a lower dose 17-β Estradiol (10µg) is now available and effectively treats healthy women with atrophic vaginitis. We hypothesized that the 10µg dose is effective and may have less systemic absorption than the 25µg dose. This is the first study to evaluate the 10µg dose in BC pts on AI therapy. Methods: A prospective longitudinal IRB-approved study was performed at MSKCC in postmenopausal women with stage I-III HR+ BC on adjuvant letrozole or anastrozole for at least 3 months and had urogenital atrophy. Patients on exemestane were not eligible due to cross-reactivity with the assay. All women were initiated on 10µg intravaginal 17- β estradiol (Vagifem®). Serial estradiol/FSH levels were measured at baseline and wks 2, 7, 12, 18 & 24; we used a highly sensitive estradiol radioimmunoassay, ESTR-US-CT, from Cisbio US, Inc. Estradiol/FSH levels were checked approximately 12 hrs after insertion, chosen to measure peak absorption. The primary endpoint was change in systemic estradiol level from baseline to wk 12. Patients also completed the Female Sexual Function Index (FSFI) and Menopausal Symptom Checklist (MSCL) at baseline and wks 12 & 24. Results: 26 pts have been treated and 18 are currently evaluable for the primary endpoint at wk 12. Wilcoxon signed rank test showed no statistically significant difference between baseline and wk 12 estradiol levels (p = 0.49) or FSH levels (p = 0.28). The median change in estradiol from baseline to wk 12 was 0.3 with a range from −3 to 14.6 (p = .49). Twelve wk results are anticipated for 6 additional pts on study; however 2 pts withdrew before wk 12. Based on the Wilcoxon signed rank test, estradiol levels were not elevated at wks 2 (n = 17) or 7 (n = 16) when compared to baseline. Graphical analysis showed a relationship with increasing estradiol coinciding with decreasing FSH, as physiologically expected. All patients reported being less bothered by menopausal symptoms on the MSCL from baseline to wk 12. Improvement in sexual function/FSFI scores was noted in all sexually active women. Conclusion: Treatment with intravaginal 10µg 17- β estradiol (Vagifem ®) did not elevate wks 2, 7 or 12 estradiol. It also provided relief of vaginal and menopausal symptoms and improvement in sexual function in postmenopausal women with HR+ BC on adjuvant AIs. This is consistent with findings in the general population. Updated data from this study will be presented for all patients treated on study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-05.