Cristiana Bergamini

High-Risk Human Papillomavirus Affects Prognosis in Patients With Surgically Treated Oropharyngeal Squamous Cell Carcinoma

PURPOSE Human papillomavirus (HPV) DNA tumors actively integrating the E6 and E7 oncogenes have a distinct biologic behavior resulting in a more favorable prognosis. To which extent the viral integration by itself, and/or the associated wild-type (wt) TP53 status, and/or a functional p16 contribute to prognosis is unclear. PATIENTS AND METHODS To clarify how the presence of high-risk (HR) -HPV, TP53, and p16INK4a status interact with clinical outcome, we considered a retrospective series of 90 consecutive oropharyngeal cancer patients treated primarily with surgery. RESULTS Seventeen (19%) patients showed integrated HPV 16 DNA (HPV positive), wt TP53 in all but two patients, normal p16INK4a in 15 assessable patients, and p16 expression in all 17 patients. Thirty-five patients (39%), two of whom were HPV positive, harbored TP53 mutations. p16INK4a deletion and p16 null immunophenotype occurred in 28 and 58 patients, respectively, and was similarly distributed in both patients with mutated TP53 (48% and 82%, respectively) and in patients with wt TP53 (46% and 77%, respectively). Statistical analysis showed that HPV-positive status significantly affects all investigated end points: overall survival (P = .0018), incidence of tumor relapse (P = .0371), and second tumor (P = .0152), whereas TP53 and p16INK4a status and p16 expression were not prognostic by themselves. CONCLUSION Our molecular and clinical results are in agreement with previous findings but provide additional information into the biologic mechanisms involved in HR-HPV oropharyngeal cancer in comparison to HPV-negative tumors. According to the reduced risk of relapse and second tumors associated with HR-HPV positivity of oropharyngeal cancer, the therapeutic strategy and follow-up procedures should be reviewed.

Cetuximab in recurrent and/or metastatic salivary gland carcinomas: A phase II study

EGFR overexpression in salivary gland carcinomas provides the rational for the investigation of anti-EGFR treatments in recurrent and/or metastatic salivary gland cancers (RMSGCs). The activity of cetuximab in terms of clinical benefit rate (CBR) defined as the occurrence of objective response (CR or PR) or stable disease (SD) for >or=6months was investigated. From April to December 2005, 30 patients [23 adenoid cystic carcinoma (ACC) and 7 non-ACC] were treated with cetuximab at 400mg/m(2)/week followed by 250mg/m(2)/week until progression, major toxicity or voluntary discontinuation. EGFR expression and gene status were retrospectively analyzed by immunocytochemistry and fluorescence in situ hybridization, respectively. A median of 14 courses of cetuximab (range 5-54) were infused. Skin toxicity was the main adverse event. Cetuximab provides a CBR in 50% (95% CL, 31 to 69%) of cases. None tumor sample showed EGFR gene amplification and an increased EGFR copy number was observed in 12% of samples, all ACC. Skin rash >or=G2, EGFR overexpression and EGFR copy number were not statistically correlated to CB. In RMSGCs further evaluations of EGFR targeting agents are advisable and should take place by appropriate tumor biological selection, differentiating ACC from non-ACC.

Treatment relevant target immunophenotyping of 139 salivary gland carcinomas (SGCs)

Salivary gland carcinomas (SGCs) are rare tumors encompassing a wide spectrum of histologic/biologic entities. Standard non-surgical treatments are ineffective in case of advanced disease. Our aim was to analyze SGCs deregulation gene profiles that could become target for innovative treatment options. Samples from 139 patients with primary, recurrent and/or metastatic SGCs were investigated by immunohistochemistry for protein encoded by tyrosine kinases receptors (TKRs) i.e. c-kit, HER2, EGFR and hormonal receptors, i.e. androgen (AR), estrogen (ER) and progesterone receptors (PgR). In 26 cases, the HER2 immunohistochemical analysis was complemented by fluorescence in-situ hybridization analysis. EGFR was the most expressed TKRs (71%) and it was found across all histotypes. c-Kit expression was mainly restricted to adenoid cystic carcinoma (78%) while HER2 expression, mostly sustained by gene amplification, correlated with salivary duct carcinoma (SDC) in 44% of cases and adenocarcinoma, not otherwise specified (AD, NOS) in 21% of cases. With respect to histogenetic classification, TKRs expression occurred more often in tumors derived from intercalated duct rather than excretory ones with the only exception of HER2. AR was found in 13% of samples, restricted to SDC and AD, NOS and it was co-expressed with HER2 in more than half of the SDC cases. ER and PgR positivity was never detected. This TK-hormonal receptors analysis identify a histotype-specific profiles that could be exploited for better selecting patients for innovative treatment within prospective studies.

Tumor stage, human papillomavirus and smoking status affect the survival of patients with oropharyngeal cancer: an Italian validation study

BACKGROUND Tumor human papillomavirus (HPV) status strongly affects overall survival (OS) of oropharyngeal cancer (OPC) patients. Recently, three groups with different outcomes were identified based on HPV status, smoking history and tumor stage. Our objective was to validate this model using a single-institutional retrospective database. PATIENTS AND METHODS Patients (n=120) diagnosed with OPC at our institution, treated with concomitant cisplatin plus radiotherapy (RT) (n=64), induction chemotherapy followed by concomitant chemoradiation (n=39) or RT alone (n=17), were stratified in three groups with respect to the risk of death (low 26, intermediate 46 and high 49 patients) according to tumor p16 expression as surrogate of HPV status, pack-years of tobacco smoking and nodal/tumor stage. Group-stratified Kaplan-Meier OS curves were estimated and compared using the log-rank test. RESULTS The 2-year OS estimates were 100%, 86% and 70%, respectively. The difference between the survival curves was statistically significant (P=0.009). The Harrells concordance index was 0.70. The calibration plot showed a good concordance between our results and those observed in the original study. CONCLUSIONS This study validates the risk grouping previously identified. Risk-driven clinical decision making and trial designs will help in better defining the most appropriate treatment in OPC patients.

Clinical activity of androgen deprivation therapy in patients with metastatic/relapsed androgen receptor–positive salivary gland cancers

Androgen deprivation therapy has some clinical activity in selected salivary gland cancer histotypes, with androgen receptor expression.

Docetaxel, cisplatin and 5-fluorouracil-based induction chemotherapy followed by intensity-modulated radiotherapy concurrent with cisplatin in locally advanced EBV-related nasopharyngeal cancer

BACKGROUND This monocentric study evaluates the activity and tolerability of docetaxel (Taxotere), cisplatin and 5-fluorouracil (5-FU) (TPF) induction chemotherapy followed by intensity-modulated radiotherapy (IMRT) concurrent with high-dose cisplatin in Epstein-Barr virus -related locally advanced undifferentiated nasopharyngeal cancer. PATIENTS AND METHODS We retrospectively reviewed the records of patients who received induction docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, and 5-FU 750 mg/m(2)/day (96-h continuous infusion). Following induction, patients received full doses of IMRT concurrently with cisplatin 100 mg/m(2) every 21 days for three cycles. RESULTS Thirty patients received three TPF cycles (median). Induction was well tolerated; the main toxicity was neutropenia (33%, grade 3-4). During chemoradiotherapy, neutropenia (40%) and mucositis (43%) were the most frequent grade 3-4 adverse events. Mean dose of IMRT was 68.8 Gy. Worst late toxicity was xerostomia. Complete response rate was 93%. At 35 months, two patients had locoregional recurrence, three had distant metastases, and one had both. Three-year progression-free survival and overall survival were 79% [95% confidence interval (CI) 64% to 94%] and 87% (95% CI 74%- to 100%), respectively. CONCLUSIONS In this high-stage nonendemic cancer population, TPF followed by high-dose cisplatin IMRT was promising; this treatment approach deserves evaluation in randomized trials.

Functional genomics uncover the biology behind the responsiveness of head and neck squamous cell cancer patients to cetuximab

Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent–metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response. Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median = 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project. Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long- and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long- versus short-PFS patients (P range: <0.0022–1e−07). Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection. Clin Cancer Res; 22(15); 3961–70. ©2016 AACR. See related commentary by Chau and Hammerman, p. 3710

Targeted therapy in head and neck cancer

Purpose of reviewResults of clinical studies on targeted cancer therapies are rapidly accumulating. This is also true in the field of head and neck cancer (HNC). Due to the unique multidisciplinary needs of the disease, it is of paramount importance that physicians who treat HNC are aware of the evolving changes that research is offering. Recent findingsMany targeted agents directed at inhibiting epithelial growth factor receptors (EGFRs) are under investigation in both curable loco-regional advanced disease in combination with standard treatments and in the recurrent metastatic setting. Human papilloma virus (HPV)-positive tumors present a distinct biological profile. Consequently, the role of targeted agents in this specific setting still needs to be refined. Herein we will briefly review the results of the most recent studies on targeted agents. Cetuximab and other monoclonal antibodies (panitumumab, zalotumumab and nimotumumab) have been already investigated in phase III studies; and some results are now available. Small molecules inhibiting EGFR have still to prove their efficacy. Other agents such as vascular endothelial cell growth factor receptor, vascular endoinsulin-like growth factor 1 receptor, MET, PI3KA and mammalian target of rapamycin inhibitor are in development. SummaryAt present treatment options in HNC are changing and include targeted agents with demonstrated efficacy. A better selection based on biological factors of patients who are potentially responsive to such targeted agents is being actively pursued.

Systemic therapy in metastatic salivary gland carcinomas: A pathology-driven paradigm?

Salivary gland carcinomas (SGCs) represent one of the most complex tumors from a pathological point of view. According to the World Health Organization (WHO) classification (2005), twenty-four malignant histotypes are recognized, almost all characterized by specific morphological and genetic features as well as by particular clinical behavior. Loco-regional relapse and distant metastases are quite common. Distant metastases are diagnosed in 25-55% of the patients and only 20% of them are alive after 5years. Adenoid cystic carcinoma (ACC) is the most common (60%) malignant histotype observed in patients with metastatic disease, whilst the other histotypes such as mucoepidermoid carcinoma, salivary duct carcinoma, adenocarcinoma, not otherwise specified (NOS), and myoepithelial carcinoma are rarer. The most common therapeutic approach in cases of metastatic disease is systemic chemotherapy, although the results with this type of approach are poor both in terms of response rate and overall outcome. No consensus has yet been reached on what the standard regimen of chemotherapy should be in this setting. New therapies are under investigation e.g. antiangiogenic agents, histone deacetylase inhibitors, and hormonal deprivation treatment. We have focused our review on systemic treatments in ACC and in non-ACC tumors, including in this latter group all SGC histotypes other than ACC.

Fentanyl pectin nasal spray as treatment for incident predictable breakthrough pain (BTP) in oral mucositis induced by chemoradiotherapy in head and neck cancer

BACKGROUND Painful mucositis is one of the most distressing toxicities of chemoradiotherapy (CRT) for head and neck cancer (HNC), with the characteristics of incidental predictable breakthrough pain (BTP) during swallowing. Fentanyl pectin nasal spray (FPNS) could be a good therapeutic option. METHODS Patients were prospectively considered if receiving basal analgesic therapy with opiates for painful mucositis of grade ⩾4 on a numerical rating scale from 0 to 10. They were offered FPNS 100mcg before oral intake. When patients reached the effective dose, they evaluated the basal pain intensity before FPNS use and after 10, 20, 30 and 40min. RESULTS Seventeen HNC patients were offered FPNS before oral intake, with 15 patients completing treatment. Mean reduction of incidental BTP intensity after FPNS was 3.1 points (range 1.2-5.8). Mean time elapsed since FPNS use and highest pain reduction was 26min. CONCLUSIONS FPNS demonstrated activity against BTP when swallowing in HNC patients. These data should be considered as hypothesis-generating.