Louis Bazire

A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes

BackgroundRadiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy. Human papillomavirus (HPV)-positive status is recognized as a marker of increased radiosensitivity. Our goal was to identify molecular markers associated with benefit to radiotherapy in patients with HPV-negative disease.MethodsGene expression profiles from public repositories were downloaded for data mining. Training sets included 421 HPV-negative HNSCC tumors from The Cancer Genome Atlas (TCGA) and 32 HNSCC cell lines with available radiosensitivity data (GSE79368). A radioresistance (RadR) score was computed using the single sample Gene Set Enrichment Analysis tool. The validation sets included two panels of cell lines (NCI-60 and GSE21644) and HPV-negative HNSCC tumor datasets, including 44 (GSE6631), 82 (GSE39366), and 179 (GSE65858) patients, respectively. We finally performed an integrated analysis of the RadR score with known recurrent genomic alterations in HNSCC, patterns of protein expression, biological hallmarks, and patterns of drug sensitivity using TCGA and the E-MTAB-3610 dataset (659 pancancer cell lines, 140 drugs).ResultsWe identified 13 genes differentially expressed between tumor and normal head and neck mucosa that were associated with radioresistance in vitro and in patients. The 13-gene expression-based RadR score was associated with recurrence in patients treated with surgery and adjuvant radiotherapy but not with surgery alone. It was significantly different among different molecular subtypes of HPV-negative HNSCC and was significantly lower in the “atypical” molecular subtype. An integrated analysis of RadR score with genomic alterations, protein expression, biological hallmarks and patterns of drug sensitivity showed a significant association with CCND1 amplification, fibronectin expression, seven hallmarks (including epithelial-to-mesenchymal transition and unfolded protein response), and increased sensitivity to elesclomol, an HSP90 inhibitor.ConclusionsOur study highlights the clinical relevance of the molecular classification of HNSCC and the RadR score to refine radiation strategies in HPV-negative disease.

Sporadic endometrial adenocarcinoma with MMR deficiency due to biallelic MSH2 somatic mutations

The invalidation of the Mismatch Repair (MMR) system is responsible for a so-called “deficient MMR” phenotype (dMMR) characterized by microsatellite instability and abnormal pattern of expression of MMR proteins in tumor tissue. This phenotype occurs in at least 20% of sporadic endometrial adenocarcinomas by epigenetic silencing of MLH1 gene. It is also observed in virtually all tumors occurring in patients with Lynch syndrome by monoallelic germline mutation in one of the MMR genes. The determination of this phenotype (dMMR vs. proficient MMR—pMMR) has therefore a pivotal place in the diagnosis algorithm for Lynch syndrome by monoallelic germline mutation in one of the MMR genes. The determination of this phenotype (dMMR vs. proficient MMR—pMMR) has therefore a pivotal place in the diagnosis algorithm for Lynch syndrome. We report the case of a woman with an early-onset endometrial adenocarcinoma who was suspected to be affected with Lynch syndrome based on tumor dMMR phenotype (MSI associated with loss of expression of MSH2 and MSH6 proteins). After complete germline and somatic evaluations, this phenotype was eventually explained by two MSH2 somatic mutations and the diagnosis of Lynch-like syndrome due to an unidentified MSH2 germline mutation was ruled out. Somatic mosaicism at low mutation rate was unlikely as no mutation was detected by DNA analysis from various tissue samples. Nevertheless, the three patient’s children were tested for the two mutations and these tests were negative. Biallelic somatic mutations of one MMR gene is a mechanism of invalidation of the MMR system in sporadic cases. Clinicians have to be aware of this mechanism because of the great clinical implication for the patients and their relatives.

The use of helical tomotherapy in the treatment of early stage breast cancer: indications, tolerance, efficacy—a single center experience

Purpose to evaluate our experience in terms of local control, survival, adverse effects in patients treated by adjuvant helical tomotherapy (HT) for breast cancer (BC). Results We studied 179 consecutive patients with 194 treated breasts with adjuvant HT. Median follow-up was 38.1 months. Median age was 53 years. Chemotherapy was administered to 83% of patients. All 133 hormone receptor positive tumours received hormonal therapy. As concurrent treatment, apart from trastuzumab monotherapy, 6 patients received systemic therapy concomitant to RT. The HT was generally well tolerated with mostly grade 1 and 2 skin reactions and esophagitis. Only 3% grade III early skin reactions. At last follow-up, there were 2 local recurrences, 1 regional lymph node (LN) recurrence and 6 with metastatic progression. The 5-year progression-free survival was 90.5% (95% CI 84.2–97.3). Materials and Methods A retrospective study of all patients treated by HT between 2009 and 2015 was done. Patients excluded were those with: breast implants, advanced or metastatic BC, recurrent disease. All patients received breast+/-boost or chest wall irradiation and most received with LN irradiation. Dose constraints for organs at risk were defined using optimization scale developed in our Department. Evaluation of early and late toxicity was done using Common Terminology Adverse Criteria Events v.4.0. Conclusions HT can be used for a well selected group of breast cancer as bilateral tumours, complex anatomy and target volumes where the conventional radiation therapy techniques cannot ensure an optimal dose distribution. Longer follow-up is necessary to confirm and validate these results.

Use of helical tomotherapy in locally advanced and/or metastatic breast cancer for locoregional treatment

OBJECTIVE Helical tomotherapy (HT) is a new promising tool whose use remains to be studied. This work assesses its impact for local irradiation in terms of side effects, as well as tumour control in locally advanced (LABC) and metastatic breast cancer (MBC). METHODS We retrospectively reviewed data of 66 patients with LABC and MBC. Patients received standard fractionated radiotherapy by HT, with or without concurrent systemic treatment. RESULTS The median age was 60 years (28-77). The median follow-up of the population was 35.9 months (10.6-95.8). For 91% of patients, HT was concomitant with systemic treatments. Three patients experienced grade 3 skin toxicity and all had concurrent 5FU-vinorelbine. One patient who was receiving concurrent treatment with trastuzumab-pertuzumab had a decreased left ventricular ejection fraction by 14%. No late cardiac or lung toxicity was observed. A clinical benefit was observed in 75% of cases. At 2 months after HT, we observed tumour regression in 7/8 patients, as following: 1 complete, 4 partial responses, and 2 stable disease. The median survival for MBC group was 64.4 months (42.6-65.8) and 21.1 (6.1-36.1) months for LABC. CONCLUSION This study suggests that the use of HT is well tolerated and feasible with a multimodal strategy that includes concurrent systemic treatments for patients with LABC and MBC. Advances in knowledge: The survival of LABC and MBC increases and new safe tools are needed to determine optimal strategies of treatment. To our knowledge, this is the first paper describing the use of HT for this population.

Patterns of loco regional failure in women with breast cancer treated by Postmastectomy Conformal Electron Beam Radiation Therapy (PMERT): Large scale single center experience

Highlights • Is a dissection of patterns of recurrence, one of rare studies in the literature, very useful for the everyday practice.• Analysis of patterns of recurrence in chest wall irradiation.

Pelvic insufficiency fracture (PIF) incidence in patients treated with intensity-modulated radiation therapy (IMRT) for gynaecological or anal cancer: single-institution experience and review of the literature

OBJECTIVE To summarize the results of pelvic insufficiency fracture (PIF) incidence in patients with anal or gynaecological cancer treated by pelvic intensity-modulated radiation therapy (IMRT). METHODS The clinical and morphological (CT and/or pelvic MRI) characteristics of patients treated by IMRT at our institution between 2007 and 2014 were analyzed. The global incidence of PIF after external beam radiotherapy and the impact of tumour site (gynaecological or anal cancer) were determined. A dosimetric study was then performed to compare patients with and without pelvic fracture. RESULTS 341 patients were treated by IMRT for gynaecological or anal cancer between 2007 and 2014. 15 patients experienced at least 1 pelvic fracture after external beam radiotherapy, corresponding to an overall incidence of 4.4%. Age and menopausal status were correlated with an increased fracture risk (p = 0.0274 and p < 0.0001, respectively). The site of the primary tumour (gynaecological or anal canal) was not associated with an excess fracture risk. The median maximum dose received at the fracture site was 50.3 Gy (range: 40.8-68.4 Gy). CONCLUSION The incidence of pelvic fracture after IMRT is low, but is higher after the age of 50 and in patients who are postmenopausal. Pre-treatment evaluation of bone density by bone densitometry and phosphorus-calcium assessment could be useful prior to the management of these patients. Advances in knowledge: Pelvic fractures are a frequent complication after radiotherapy. The influence of IMRT and clinical characteristics were evaluated in this study.