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Background Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) have a poor prognosis and limited therapeutic options. Immune checkpoint inhibitors (ICIs) are effective in patients with tumor progression < 6 months following first-line, platinum-based chemotherapy (PBC), but data are missing for patients with progression ≥ 6 months after the last platinum dose. Methods Retrospective analysis (six French centers, 2008–2019) of all consecutive R/M-HNSCC patients. treated first-line with PBC and tumor progression ≥ 6 months after the last platinum dose. Primary endpoint: progression-free survival after second-line therapy (PFS2). Additional endpoints: overall survival from Day 1 of first-line (OS1) and second-line (OS2) therapy. Results R/M-HNSCC patients (n = 144) received cisplatinum (n = 67, 47%) or carboplatinum (n = 77, 53%) first-line. Response after first-line: complete response (CR; n = 16, 11%); partial response (PR; n = 77, 53%); stable disease (n = 22, 15%). Second-line therapy: PBC (n = 95, 66%); platinum-free regimen (PFR) (n = 25, 17%); ICI (n = 24, 17%). Median [95% confidence interval] PFS (months): PBC 5.0 [3.8–6.2]; PFR 4.0 [1–7.0]; ICI 2.0 [0.4–3.6] (p = 0.16). For PBC, PFR, and ICI, respectively: OS1 30, 23, and 29 months (p = 1.02); OS2 14, 10, and 16 months (p = 0.25); PR, 26%, 16%, and 21% patients; CR, 0%, 8%, and 4% patients. For subsequent lines, ICIs were administered for PBC (n = 11, 12%) and PFR (n = 2, 8%). No predictive factor for efficacy (PFS, OS) was identified. Conclusions Our retrospective study suggests similar efficacy regarding OS2 for second-line chemotherapy or ICI in R/M-HNSCC patients with progression ≥ 6 months after the last first-line platinum dose.

The response to immunotherapy has been little investigated in overweight and obese cancer patients. We evaluated the relationships between BMI, toxicity, and survival in patients treated by immunotherapy for metastatic cancer. We included metastatic cancer patients treated by immunotherapy between January 2017 and June 2020 at the Centre Léon Bérard. In total, 272 patients were included: 64% men and 36% women, with a median age of 61.4 years. BMI ≥ 25 in 34.2% and 50% had non-small cell lung cancer (n = 136). Most received monotherapy, with nivolumab in 41.9% and pembrolizumab in 37.9%. Toxicity, mostly dysthyroiditis, occurred in 41%. Median overall survival (OS), estimated by Kaplan–Meier analysis, was significantly longer for patients with a BMI ≥ 25 than for those with a BMI < 25 (24.8 versus 13.7 months HR = 0.63; 95% CI 0.44–0.92, p = 0.015), and for patients experiencing toxicity than for those without toxicity (NR versus 7.8 months, HR = 0.22; 95% CI 0.15–0.33, p < 0.001). Adjusted OS was associated with toxicity, and the occurrence of toxicity was associated with sex and histological features but not with BMI. Thus, being overweight and experiencing toxicity was associated with longer overall survival in patients treated by immunotherapy. More attention should be paid to body composition in the care of cancer patients.

Triple negative breast cancer (TNBC) is a highly heterogeneous disease with a poor prognosis and a paucity of therapeutic options. In recent years, immunotherapy has emerged as a new treatment option for patients with TNBC. However, this therapeutic evolution is paralleled by a growing need for biomarkers which allow for a better selection of patients who are most likely to benefit from this immune checkpoint inhibitor (ICI)-based regimen. These biomarkers will not only facilitate a better optimization of treatment strategies, but they will also avoid unnecessary side effects in non-responders, and limit the increasing financial toxicity linked to the use of these agents. Huge efforts have been deployed to identify predictive biomarkers for the ICI, but until now, the fruits of this labor remained largely unsatisfactory. Among clinically validated biomarkers, only programmed death-ligand 1 protein (PD-L1) expression has been prospectively assessed in TNBC trials. In addition to this, microsatellite instability and a high tumor mutational burden are approved as tumor agnostic biomarkers, but only a small percentage of TNBC fits this category. Furthermore, TNBC should no longer be approached as a single biological entity, but rather as a complex disease with different molecular, clinicopathological, and tumor microenvironment subgroups. This review provides an overview of the validated and evolving predictive biomarkers for a response to ICI in TNBC.

Recently, OlympiAD and EMBRACA trials demonstrated the favorable efficacy/toxicity ratio of PARPi, compared to chemotherapy, in patients with HER2-negative metastatic breast cancers (mBC) carrying a germline BRCA mutation. PARPi have been largely adopted in triple-negative metastatic breast cancer, but their place has been less clearly defined in endocrine-receptor positive, HER2 negative (ER+/ HER2-) mBC. The present narrative review aims at addressing this question by identifying the patients that are more likely benefit from PARPi. Frequencies of BRCA pathogenic variant (PV) carriers among ER+/HER2- breast cancer patients have been underestimated, and many experts assume than 50% of all BRCA1/2 mutated breast cancers are of ER+/HER2- subtype. Patients with ER+/HER2- BRCA-mutated mBC seemed to have a higher risk of early disease progression while on CDK4/6 inhibitors and PARPi are effective especially when prescribed before exposure to chemotherapy. The OLYMPIA trial also highlighted the utility of PARPi in patients with early breast cancers at high risk of relapse and carrying PV of BRCA. PARPi might also be effective in patients with HRD diseases, representing up to 20% of ER+/HER2- breast cancers. Consequently, the future implementation of early genotyping strategies for identifying the patients with high-risk ER+/HER2- HRD breast cancers likely to benefit from PARPi is of high importance.

ObjectiveTreatment of high-grade serous ovarian carcinomas relies on surgery and chemotherapy, potentially followed by bevacizumab and/or poly (ADP-ribose) polymerase inhibitors (PARPi). The modeled CA-125 ELIMination rate constant K (KELIM) is a pragmatic indicator of tumor primary chemosensitivity. Although it is well established that BRCA mutations are associated with platinum sensitivity, the relationship between BRCA status and KELIM score has yet to be elucidated. This study aimed to evaluate the interactions between BRCA and KELIM, and their respective prognostic values.MethodsWe retrospectively collected data from 743 patients with high-grade serous ovarian carcinomas included in a French nationwide registry (NCT03275298) treated with neoadjuvant platinum-based chemotherapy followed by surgery. We analyzed the interactions between BRCA and KELIM, and their impacts on progression-free survival and overall survival.ResultsBRCA-mutated (BRCAm) patients had higher standardized KELIM than BRCA-wild type (BRCAwt) tumors (median 1.16 vs 1.06, respectively; p=0.001). The prognostic value of the KELIM score was independent of BRCA in multivariate analyses. KELIM score and BRCA could be combined to define three prognostic groups: (1) an unfavorable prognostic group with both BRCAwt and unfavorable KELIM (median progression-free survival 12.0 months); (2) an intermediate prognostic group with either BRCAm and unfavorable KELIM, or BRCAwt and favorable KELIM (median progression-free survival of 16.0 and 18.8 months, respectively; HR 0.64 compared with the unfavorable group, p<0.001); and (3) a favorable prognostic group with both BRCAm and favorable KELIM (median progression-free survival 28.8 months; HR 0.37 compared with the unfavorable group, p<0.001).ConclusionsThe KELIM score provides complementary prognostic information with respect to BRCA, and discriminates different prognoses within BRCAm or BRCAwt patients. Patients with both BRCAwt/unfavorable KELIM have a poor prognosis, underscoring the urgent need for novel therapeutic strategies.

ObjectivesWhile some metals have been reported as carcinogens or potential carcinogens, only few modern-standard datasets including a large number of elements are available. The present analysis established a first trace elements spectrum by relating the concentration of metals and trace elements in the serum of sarcoma patients with survival data.MethodsPatients with sarcoma and controls were retrospectively selected from the International Sarcoma Kindred Study database (ISKS). As part of the ISKS study, blood samples were prospectively collected at the Leon Bérard Cancer Center from February 2012 to July 2019. Stable specimens and copper isotopes (65Cu/63Cu) were analyzed using Triple Quadrupole Inductively Coupled Plasma Mass Spectrometer (ICP-MS) and the Multicollector MC-ICP-MS Nu Plasma HR 500. Wilcoxon rank sum test, log-rank test, and multivariate Cox regression models were used for statistics.ResultsIn total, 151 patients and 59 healthy controls were included. At the time of blood sample collection, 62% of patients had locally advanced or metastatic disease. Copper (Cu), copper/zinc (Cu/Zn) and potassium/rubidium (K/Rb) ratio were significantly higher in patients compared to controls and were also significantly higher in patients with advanced compared to early-stage sarcoma. Whereas S and Se were significantly correlated in patients, no correlation was observed in controls. Importantly, levels of K, Rb, Se, Fe, P, Si, S, δ65Cu, Cu, S/Se and Cu/Zn ratio were independently associated with overall survival.ConclusionsThese results depict the metallomic spectrum in sarcoma and highlight substantial variation associated with survival, enhancing our understanding of sarcoma’s biology.

Background: Poly(ADP-ribose) polymerase 1 inhibitor (PARPi) agents can improve progression-free survival of patients with breast cancer who carry a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant (gBRCA) in both the metastatic and adjuvant setting. Therefore, we need to reassess the frequency of gBRCA1 and gBRCA2 in order to redefine the criteria for women and tumor phenotype that should be tested. Objective: We studied the relative distribution of gBRCA1 and gBRCA2 in unselected populations of women with breast cancer and in unaffected individuals. We also analyzed the proportion of estrogen receptor (ER)-positive (ER+) tumors in unselected breast cancer patients with gBRCA. Design: We performed a meta-analysis of studies of unselected breast cancer that analyzed the relative contribution of gBRCA1 versus gBRCA2 among unselected breast cancer cases in gBRCA carriers. We then performed a meta-analysis of gBRCA carriage in unaffected individuals from genome-wide population studies, the gnomAD databank, and case–control studies. Results: The BRCA2 gene was involved in 54% of breast cancer cases in unselected patients with gBRCA (n = 108,699) and 60% of unaffected individuals (n = 238,973) as compared with 38% of the largest gBRCA family cohort (n = 29,700). The meta-analysis showed that 1.66% (95% CI 1.08–2.54) and 1.71% (95% CI 1.33–2.2) of unselected breast cancer patients carried gBRCA1 and gBRCA2, respectively. In a population of unaffected individuals, the frequency of heterozygosity for gBRCA1 and gBRCA2 was estimated at 1/434 and 1/288, respectively. Nearly 0.5% of unaffected individuals in the studied populations carried a gBRCA. Carriage of a gBRCA was 2.5% for patients with ER+ tumors (95% CI 1.5–4.1) and 5.7% (95% CI 5.1–6.2) for those with ER- tumors. Overall, 58% of breast tumors occurring in women carrying a gBRCA were ER+ (n = 86,870). Conclusions: This meta-analysis showed that gBRCA2 carriage is predominant in unselected breast cancer patients and unaffected individuals. ER+ tumors among women with gBRCA-related breast cancer are predominant and have been underestimated. Because PARPi agents improve progression-free survival with ER+ gBRCA breast cancer in most clinical trials, breast cancer should be considered, regardless of ER status, for BRCA1/2 screening for therapeutic purposes.

ObjectiveTo evaluate the incidence and risk factors for ICE during a PV.Materials and methodsSingle-center retrospective analysis of 1512 consecutive patients who underwent 1854 PV procedures for osteoporotic (34 %), malignant (39.9 %) or other cause (26.1 %) of vertebral compression fractures (VCFs)/spine tumor lesions. Only thoracic or lumbar PVs were included. PVs were performed with polymethylmethacrylate (PMMA) low-viscosity bone cement under fluoroscopic guidance. Chest imaging (X-ray or CT) was performed the same day after PV in patients with high clinical suspicion of ICE. All post-procedural chest-imaging examinations were reviewed, and all ICEs were agreed upon in consensus by two radiologists.ResultsICEs were detected in 72 patients (92 cement embolisms). In 86.1 % of the cases, concomitant pulmonary artery cement leakage was detected. Symptomatic ICEs were observed in six cases (8.3% of all ICEs; 0.32% of all PV procedures). No ICE led to death or permanent sequelae. Multiple levels treated during the same PV session were associated with a higher ICE rate [OR: 3.59, 95% CI: (1.98-6.51); p < 0.001]; the use of flat panel technology with a lower ICE occurrence [OR: 0.51, 95% CI: (0.32-0.83); p = 0.007].ConclusionIntracardiac cement embolism after PV has a low incidence (3.9 % in our study). Symptomatic complications related to ICE are rare (0.3%); none was responsible for clinical sequelae in our series.Key Points• The incidence of intracardiac cement embolism (ICE) during PVP is low (3.9%).• Having a high number of treated vertebrae during the same session is a significant risk factor for ICE.• Symptomatic intracardiac cement embolisms have a low incidence (8.3% of patients with ICE).

CD95 is a death receptor that can promote oncogenesis through molecular mechanisms that are not fully elucidated. Although the mature CD95 membrane receptor is considered to start with the arginine at position 17 after elimination of the signal peptide, this receptor can also be cleaved by MMP7 upstream of its leucine at position 37. This post-translational modification occurs in cancer cells but also in normal cells such as peripheral blood leukocytes. The non-cleaved CD95 amino-terminal region consists in a disordered domain and its in silico reconstitution suggests that it might contribute to receptor aggregation and thereby, regulate the downstream death signaling pathways. In agreement with this molecular modeling analysis, the comparison of CD95-deficient cells reconstituted with full-length or N-terminally truncated CD95 reveals that the loss of the amino-terminal region of CD95 impairs the initial steps of the apoptotic signal while favoring the induction of pro-survival signals, including the PI3K and MAPK pathways.

Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype–genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype–genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.