Shira Abberbock

Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium

The advent of effective targeted therapy for BRAFV600E‐mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced‐stage BRAF‐mutant lung adenocarcinomas.

Transoral Robotic Surgery Alone for Oropharyngeal Cancer: Quality-of-Life Outcomes

IMPORTANCE Few studies have examined quality-of-life (QOL) outcomes in patients who undergo transoral robotic surgery (TORS) alone (ie, without adjuvant radiotherapy or chemoradiotherapy). OBJECTIVE To report QOL outcomes of patients with oropharyngeal squamous cell carcinoma who receive only TORS. DESIGN, SETTING, AND PARTICIPANTS Medical records for all patients undergoing TORS for treatment of primary oropharyngeal squamous cell carcinoma from May 1, 2010, to March 31, 2014, at a tertiary care academic cancer center were examined from June through September 2014. Thirty-four patients who did not receive adjuvant therapy after TORS were included in the study. INTERVENTION Primary surgical resection via TORS. MAIN OUTCOMES AND MEASURES The University of Washington Quality of Life, version 4, questionnaire was completed by patients preoperatively and at 1-, 6-, 12-, and 24-month intervals after TORS. Demographic, clinicopathologic, and follow-up data were collected. RESULTS Mean follow-up time was 14 months (May 1, 2010, to April 30, 2014). Most patients had T1 (20 [59%]) or T2 (13 [38%]) and N0 (13 [38%]) or N1 (16 [47%]) disease. Statistically significant improvement in QOL outcomes was noted in the following postoperative domains: chewing from 1 month (median, 50 [IQR, 50-100]) to 12 months (100 [IQR, 100-100]; P = .048), swallowing from 1 month (70 [IQR, 30-85]) to 6 months (100 [IQR, 70-100]; P = .047) and 1 to 24 months (100 [IQR, 70-100]; P = .048), pain from 1 month (38 [IQR, 25-75]) to 6 months (88 [IQR, 75-100]; P = .006) and 1 to 12 months after surgery (100 [IQR, 75-100]; P = .01), and activity from 1 month (63 [IQR, 50-88]) to 24 months (100 [IQR, 75-100]; P = .03). Two participants (6%) died during the follow-up period: 1 because of disease and 1 because of a myocardial infarction. Two patients (6%) required temporary gastrostomy tube placement, but none required tracheostomy. CONCLUSIONS AND RELEVANCE Appropriately selected patients who undergo TORS alone for oropharyngeal squamous cell carcinoma experience acceptable short- and long-term QOL outcomes.

ALK FISH patterns and the detection of ALK fusions by next generation sequencing in lung adenocarcinoma

Break-apart ALK FISH probe is the FDA approved approach for detection of ALK rearrangements in lung carcinoma patients who may benefit from ALK kinase inhibitors. The FISH assay can be technically challenging and difficult to interpret. ALK immunohistochemistry and next generation sequencing have been proposed as alternative approaches. In this study, we compared various ALK –FISH patterns to next –generation sequencing (NGS) for gene fusion detection, ALK immunohistochemistry (IHC) and tumor responses to crizotinib. 72 (4%) of 2116 lung adenocarcinoma were positive by ALK- FISH. Of 28 ALK-FISH positive cases selected for the study, FISH patterns included 15 (54%) cases with split signal, 10 (36%) with single orange signal and 3 (10%) with “mixed pattern”. 12 (80%) cases with split signal and 4 (40%) cases with single orange signal were positive by NGS and IHC, while mixed cases were all negative. Mutation analysis of discordant cases revealed multiple mutations including oncogenic mutations in EGFR, KRAS, BRAF and ATM genes. All discordant cases in groups with split and mixed signal showed a lower number of cells with rearrangement (mean 28.5%; range 20.5-36.9%). No statistically significant association between response to crizotinib and FISH patterns was observed (p=0.73). In contrast, NGS fusion positive cases were associated with more responses to crizotinib than NGS negative cases (p= 0.016). Our study suggests that ALK FISH alone may not be the most reliable assay for detection of ALK gene rearrangements, and probably should be used in parallel with ALK IHC and NGS for detection of gene fusions and mutations.

Selection of Ideal Candidates for Surgical Salvage of Head and Neck Squamous Cell Carcinoma: Effect of the Charlson-Age Comorbidity Index and Oncologic Characteristics on 1-Year Survival and Hospital Course.

IMPORTANCE Salvage surgery for recurrent head and neck squamous cell carcinoma (HNSCC) carries substantial risks of morbidity and mortality. Risk factors for death within 1 year should be better defined. OBJECTIVES To report preoperative oncologic prognostic factors predictive of short-term (<1 year) survival after salvage surgery in patients with HNSCC, to assess whether preoperative age and comorbidity predicts 1-year mortality, and to report hospital courses after salvage surgery within 1 year. DESIGN, SETTING, AND PARTICIPANTS A retrospective medical record review of 191 patients with recurrent HNSCC treated with salvage surgery from January 1, 2003, through December 31, 2013, at a tertiary academic center. INTERVENTIONS Surgical salvage of HNSCC (larynx, oral cavity, oropharynx, or hypopharynx) with curative intent. MAIN OUTCOMES AND MEASURES Primary outcome was survival 1 year after salvage surgery. Secondary outcomes were length of inpatient hospital stay, days of admissions, and skilled nursing facility disposition within 1 year stratified by survival status. Presalvage Charlson-Age Comorbidity Index (CACI) was calculated. Associations among CACI, oncologic risk factors, and risk of death within 1 year after salvage surgery are investigated using multivariable analysis. RESULTS Of 191 patients studied, 53 (27.7%) died within 1 year after salvage surgery. Patients who died within 1 year had more total inpatient admissions (P < .001), longer total length of stay (P < .001), and higher risk of discharge to a skilled nursing facility (P < .001) and spent 17.3% (interquartile range, 5.2-36.3) of their remaining days in the hospital. Independent risk factors for death within 1 year are CACI (relative risk [RR], 1.43; 95% CI, 1.16-1.76), primary T3 or T4 stage (RR, 2.34; 95% CI, 1.27-4.31), and disease-free interval of less than 6 months (RR, 5.61; 95% CI, 1.78-16.7). CONCLUSIONS AND RELEVANCE Medical comorbidity and age as measured by the CACI, primary T3 or T4 stage, and short disease-free interval must be considered in selecting patients ideal for surgical salvage surgery for recurrent HNSCC. Patients with these risk factors should be more strongly considered for palliative measures.

Utility of up-front transoral robotic surgery in tailoring adjuvant therapy.

The purpose of this study was to describe how the up‐front transoral robotic surgery (TORS) approach could be used to individually tailor adjuvant therapy based on surgical pathology.

Adenosquamous carcinoma of the head and neck: Molecular analysis using CRTC-MAML FISH and survival comparison with paired conventional squamous cell carcinoma

Adenosquamous carcinoma (ASC) is a rare variant of head‐and‐neck squamous cell carcinoma (HNSCC) generally thought to be uniformly aggressive with poor prognosis. However, it remains unknown how overall survival compare with conventional HNSCC. Here we report for the first time that ASC does not necessarily indicate a worse prognosis than conventional HNSCC.

Parametric Response Mapping of Apparent Diffusion Coefficient as an Imaging Biomarker to Distinguish Pseudoprogression from True Tumor Progression in Peptide-Based Vaccine Therapy for Pediatric Diffuse Intrinsic Pontine Glioma

BACKGROUND AND PURPOSE: Immune response to cancer therapy may result in pseudoprogression, which can only be identified retrospectively and may disrupt an effective therapy. This study assesses whether serial parametric response mapping (a voxel-by-voxel method of image analysis also known as functional diffusion mapping) analysis of ADC measurements following peptide-based vaccination may help prospectively distinguish progression from pseudoprogression in pediatric patients with diffuse intrinsic pontine gliomas. MATERIALS AND METHODS: From 2009 to 2012, 21 children, 4–18 years of age, with diffuse intrinsic pontine gliomas were enrolled in a serial peptide-based vaccination protocol following radiation therapy. DWI was acquired before immunotherapy and at 6-week intervals during vaccine treatment. Pseudoprogression was identified retrospectively on the basis of clinical and radiographic findings, excluding DWI. Parametric response mapping was used to analyze 96 scans, comparing ADC measures at multiple time points (from the first vaccine to up to 12 weeks after the vaccine was halted) with prevaccine baseline values. Log-transformed fractional increased ADC, fractional decreased ADC, and parametric response mapping ratio (fractional increased ADC/fractional decreased ADC) were compared between patients with and without pseudoprogression, by using generalized estimating equations with inverse weighting by cluster size. RESULTS: Median survival was 13.1 months from diagnosis (range, 6.4–24.9 months). Four of 21 children (19%) were assessed as experiencing pseudoprogression. Patients with pseudoprogression had higher fitted average log-transformed parametric response mapping ratios (P = .01) and fractional decreased ADCs (P = .0004), compared with patients without pseudoprogression. CONCLUSIONS: Serial parametric response mapping of ADC, performed at multiple time points of therapy, may distinguish pseudoprogression from true progression in patients with diffuse intrinsic pontine gliomas treated with peptide-based vaccination.

Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma

Significance Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant lung adenocarcinoma remains an intractable lung cancer subtype for which efficacious targeted therapies do not exist. This study identified a subpopulation of KRAS mutant lung adenocarcinoma with reduced insulin receptor substrate-1 (IRS-1) content and showed that this group is particularly amenable to Janus kinase/signal transducers and activators of transcription (JAK/STAT) inhibition. This finding is the first definitive report of a prohost role for IRS-1 in a solid tumor malignancy in humans. Furthermore, the data supports a novel role for IRS-1 in the sculpting of immune cell composition within the tumor microenvironment. Insulin receptor substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many pathways activated in lung cancer. It has been assumed that IRS-1 promotes tumor growth through its ability to activate PI3K signaling downstream of the insulin-like growth factor receptor. Surprisingly, tumors with reduced IRS-1 staining in a human lung adenocarcinoma tissue microarray displayed a significant survival disadvantage, especially within the Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant subgroup. Accordingly, adenoviral Cre recombinase (AdCre)-treated LSL-Kras/Irs-1fl/fl (Kras/Irs-1−/−) mice displayed increased tumor burden and mortality compared with controls. Mechanistically, IRS-1 deficiency promotes Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling via the IL-22 receptor, resulting in enhanced tumor-promoting inflammation. Treatment of Kras/Irs-1+/+ and Kras/Irs-1−/− mice with JAK inhibitors significantly reduced tumor burden, most notably in the IRS-1-deficient group.

Association of pretreatment body mass index and survival in human papillomavirus positive oropharyngeal squamous cell carcinoma

BACKGROUND Pretreatment body mass index (BMI) >25kg/m(2) is a positive prognostic factor in patients with head and neck cancer. Previous studies have not been adequately stratified by human papilloma virus (HPV) status or subsite. Our objective is to determine prognostic significance of pretreatment BMI on overall survival in HPV+ oropharyngeal squamous cell carcinoma (OPSCC). METHODS This is a retrospective review of patients with HPV+ OPSCC treated between 8/1/2006 and 8/31/2014. Patients were stratified by BMI status (>/<25kg/m(2)). Univariate and multivariate analyses of survival were performed. RESULTS 300 patients met our inclusion/exclusion criteria. Patients with a BMI >25kg/m(2) had a longer overall survival (HR=0.49, P=0.01) as well as a longer disease-specific survival (HR=0.43, P=0.02). Overall survival remained significantly associated with high BMI on multivariate analysis (HR=0.54, P=0.04). CONCLUSIONS Pre-treatment normal or underweight BMI status is associated with worse overall survival in HPV+ OPSCC.

ATM protein is deficient in over 40% of lung adenocarcinomas

Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000s of patients with ATM-deficient lung adenocarcinoma every year.