Carlo Resteghini

Prognostic and predictive value of EGFR in head and neck squamous cell carcinoma

EGFR is an extensively studied biomarker in head and neck squamous cell carcinoma (HNSCC). In this review, we discuss the prognostic and predictive role of EGFR in HNSCC, focusing on the different molecular alterations in specific treatment modalities such as radiotherapy alone (RT), combination of surgery, RT and chemotherapy (CT), EGFR inhibitors. We considered EGFR at different molecular levels: protein expression, protein activation, gene copy number, polymorphisms, mutation, EGFRvIII expression and EGFR ligand expression. Considering RT alone, evidence supports the predictive and prognostic role of high EGFR expression only when evaluated by quantitative assays: this may help select the patients who can mostly benefit from accelerated treatment. Conversely, no predictive biomarkers are available when treatment is a combination of surgery, CT and RT. For this combined treatment, several studies indicate that EGFR expression represents a good prognostic parameter only when measured by a “quantitative” or at least semi-quantitative method. With respect to EGFR inhibitors, neither EGFR expression nor increased gene copy number represent prognostic/predictive factors. If validated, nuclear EGFR, TGFα levels, EGFR phopshorylation and polymorphisms could represent additional prognostic factors in relation to combination of surgery, CT and RT, while EGFR polymorphisms and high amphiregulin levels could have prognostic value in patients treated with EGFR inhibitors.

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.

Does a multidisciplinary team approach in a tertiary referral centre impact on the initial management of head and neck cancer

OBJECTIVES A multi-disciplinary team (MDT) is essential in the management of cancer. Head and neck cancer (HNC) is a rare, complex and heterogeneous group of malignancies for which different treatment options are available. However, the potential impact of MDT on the management of HNC has been only poorly evaluated to date. This study evaluates the impact of MDT on the management of HNC in a tertiary centre. METHODS We retrospectively analysed records of HNC patients referred to a MDT evaluation at the Istituto Nazionale Tumori of Milan, Italy, from May 2007 to January 2012. All cases were reviewed by a MDT consisting of a head and neck surgeon, a radiation oncologist, and a medical oncologist. RESULTS Data from 781 HNC patients were analysed. Approximately 70% of patients were referred to our Institution for a second opinion consultation. Following MDT evaluation, new staging examinations were requested in 49% of patients, and treatment plan was modified in 10%. CONCLUSIONS A MDT approach in a tertiary referral hospital leads to staging refinement of disease or changes in treatment plan in about 60% of patients.

Temporal course and predictive factors of analgesic opioid requirement for chemoradiation-induced oral mucositis in oropharyngeal cancer

Oral mucositis (OM)‐related pain affects most patients with head and neck cancer during treatments, but its management is not standardized.

Circulating pre-treatment Epstein-Barr virus DNA as prognostic factor in locally-advanced nasopharyngeal cancer in a non-endemic area

The prognostic value of pre-treatment Epstein-Barr Virus (EBV) DNA viral load for non-endemic, locally-advanced, EBV-related nasopharyngeal cancer (NPC) patients is yet to be defined. All patients with EBV encoded RNA (EBER)-positive NPC treated at our Institution from 2005 to 2014 with chemotherapy (CT) concurrent with radiation (RT) +/- induction chemotherapy (ICT) were retrospectively reviewed. Pre-treatment baseline plasma EBV DNA (b-EBV DNA) viral load was detected and quantified by PCR. Median b-EBV DNA value was correlated to potential influencing factors by univariate analysis. Significant variables were then extrapolated and included in a multivariate linear regression model. The same variables, including b-EBV DNA, were correlated with Disease Free Survival (DFS) and Overall Survival (OS) by univariate and multivariate analysis. A total of 130 locally-advanced EBER positive NPC patients were evaluated. Overall, b-EBV DNA was detected in 103 patients (79.2%). Median viral load was 554 copies/mL (range 50–151075), and was positively correlated with T stage (p=0.002), N3a-b vs N0-1-2 stage (p=0.048), type of treatment (ICT followed by CTRT, p=0.006) and locoregional and/or distant disease recurrence (p=0.034). In the overall population, DFS and OS were significantly longer in patients with pre-treatment negative EBV DNA than in positive subjects at the multivariate analysis. Negative b-EBV DNA can be considered as prognostic biomarker of longer DFS and OS in NPC in non-endemic areas. This finding needs confirmation in larger prospective series, with standardized and inter-laboratory harmonized method of plasma EBV DNA quantification.

Outcome of recurrent and metastatic head and neck squamous cell cancer patients after first line platinum and cetuximab therapy

OBJECTIVES Second-line chemotherapy in recurrent and/or metastatic head and neck cancer (r/mHNSCC) patients showed dismal results with limited tumor response and reduced life expectancy. Outside of clinical trials, data on efficacy of second line treatment after first line anti-EGFR-AB combination therapy are not available. MATERIAL AND METHODS Data regarding r/mHNSCC consecutive pts treated with cetuximab and platinum from 2009 to 2014 at our center were retrospectively collected. The analyses of response, Progression-Free Survival (PFS) and Overall Survival (OS), each evaluated starting from first and second-line treatment, were performed. Survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. RESULTS We identified 117 patients treated with first-line platinum and cetuximab-based therapy. Sixty-four (55%) patients did not receive second-line treatment due to worsening in performance status, 2 were not assessable for response thus 51 patients were included for analysis. Fifty-six percent were smokers/former smokers and 78% were male. Primary tumor sites were oropharynx (39%), oral cavity (31%), larynx/hypopharynx (24%) and others (6%). Regimens used in second-line were mostly monotherapies. Twenty-one % of the patients were treated within a clinical trial. Response rate (PR, CR) was 6% with 45% showing SD as best response. Median PFS was 2.2months (95%CI:1.5-2.8months) and OS 6.1months (95%CI:3.7-7.2months). CONCLUSIONS Within our single center experience only half of the patients with r/mHNSCC were able to receive second-line treatment. Response rate was unsatisfactory, but median OS seems higher than previously reported in an anti-EGFR-AB naïve population (Leon 2005).

Prognostic role of PIK3CA and TP53 in human papillomavirus–negative oropharyngeal cancers:

Background: Human papilloma virus (HPV)–negative oropharyngeal squamous cell carcinomas (OPCs) have a poorer prognosis and best management is an unmet need. We studied the prognostic role of epidermal growth factor receptor (EGFR) and PIK3CA amplifications and TP53 functional status. Methods: Between 1992 and 2000, 90 consecutive patients with OPCs were treated with surgery, followed by radiotherapy in case of high-risk pathologic features. Of those, 73 cases were HPV-negative and therefore were selected for molecular analysis (PIK3CA and EGFR fluorescent in situ hybridization [FISH] analysis and TP53 mutation analysis). Results: FISH analyses of EGFR and PIK3CA were successfully conducted on 69 and 63 of 73 tumor samples, respectively. EGFR alterations were detected in 43% of patients but just 7% showed amplification. Seven cases (11%) carried PIK3CA amplification and 18 (29%) gene gain or high polysomy. TP53 was detected as nonfunctional in 24 of 67 (36%) successfully analyzed cases. Both univariable and multivariable analysis showed statistically significantly worse disease-free survival (DFS) for patients with PIK3CA disomy compared to those with gene gain or high polysomy. No differences in overall survival or DFS for EGFR and TP53 alteration were evident. The combined evaluation of PIK3CA and TP53 showed that PIK3CA gene copy number gain separated a population with better outcome, defining an overall worse prognosis population (disomy) now clearly further divided according to TP53 functional status. Conclusion: PIK3CA gene copy number increase is associated with a favorable clinical outcome in HPV-negative OPCs treated with surgery ± postoperative radiotherapy. In patients without PIK3CA alteration, TP53 nonfunctional mutations are associated with poor prognosis.

Big Data in Head and Neck Cancer

Opinion statementHead and neck cancers can be used as a paradigm for exploring “big data” applications in oncology. Computational strategies derived from big data science hold the promise of shedding new light on the molecular mechanisms driving head and neck cancer pathogenesis, identifying new prognostic and predictive factors, and discovering potential therapeutics against this highly complex disease. Big data strategies integrate robust data input, from radiomics, genomics, and clinical-epidemiological data to deeply describe head and neck cancer characteristics. Thus, big data may advance research generating new knowledge and improve head and neck cancer prognosis supporting clinical decision-making and development of treatment recommendations.

RANK expression in EBV positive nasopharyngeal carcinoma metastasis: a ready-to-treat target?

Epstein Barr Virus (EBV) related Nasopharyngeal Carcinoma (NPC), is an highly chemo- and radiosensitive endemic malignancy in southeast Asia. More than one third of locally advanced cases relapse after curative treatment, especially because of bone, liver and lung metastases. Lymphocyte sub-populations favour EBV-associated carcinogenesis and tumour progression and several strategies aim to reverse this phenomenon. Receptor activator of NF-kB (RANK) and its Ligand (RANKL), key regulator of bone metabolisms, are expressed in several malignancies and tumor-infiltrating Tregs. We collected 17 paired FFPE specimen of primary and metachronous metastatic or regionally relapsed EBV related NPC and evaluated RANK expression by immunohistochemistry. All primary tumour specimens resulted not evaluable whereas all metastatic specimens, regardless of sites, showed high RANK IHC expression in the tumor with no staining in normal surrounding tissues. This observation deserves further clarifications and could open the way to trials testing the hypotesis that targeting the RANK/RANKL pathway with denosumab, an already available, clinically approved monoclonal antibody for metastatic bone lesions, might restore proper anti-tumor immune response in NPC metastatic patients.