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Abstract Background Neoadjuvant chemotherapy (NACT) became a standard treatment strategy for patients with inflammatory breast cancer (IBC) because of high disease aggressiveness. However, given the heterogeneity of IBC, no molecular feature reliably predicts the response to chemotherapy. Whole-exome sequencing (WES) of clinical tumor samples provides an opportunity to identify genomic alterations associated with chemosensitivity. Methods We retrospectively applied WES to 44 untreated IBC primary tumor samples and matched normal DNA. The pathological response to NACT, assessed on operative specimen, distinguished the patients with versus without pathological complete response (pCR versus no-pCR respectively). We compared the mutational profiles, spectra and signatures, pathway mutations, copy number alterations (CNAs), HRD, and heterogeneity scores between pCR versus no-pCR patients. Results The TMB, HRD, and mutational spectra were not different between the complete (N = 13) versus non-complete (N = 31) responders. The two most frequently mutated genes were TP53 and PIK3CA. They were more frequently mutated in the complete responders, but the difference was not significant. Only two genes, NLRP3 and SLC9B1, were significantly more frequently mutated in the complete responders (23% vs. 0%). By contrast, several biological pathways involved in protein translation, PI3K pathway, and signal transduction showed significantly higher mutation frequency in the patients with pCR. We observed a higher abundance of COSMIC signature 7 (due to ultraviolet light exposure) in tumors from complete responders. The comparison of CNAs of the 3808 genes included in the GISTIC regions between both patients’ groups identified 234 genes as differentially altered. The CIN signatures were not differentially represented between the complete versus non-complete responders. Based on the H-index, the patients with heterogeneous tumors displayed a lower pCR rate (11%) than those with less heterogeneous tumors (35%). Conclusions This is the first study aiming at identifying correlations between the WES data of IBC samples and the achievement of pCR to NACT. Our results, obtained in this 44-sample series, suggest a few subtle genomic alterations associated with pathological response. Additional investigations are required in larger series.

BackgroundElderly breast cancer (BC) patients have been underrepresented in clinical trials whereas ~60% of deaths from BC occur in women aged 70 years and older. Only limited data are available on the prognostic impact of age according to treatment, especially in the triple-negative (TN) and Her2-positive because of the lower frequency of these subtypes in elderly patients. We report herein the results of a multicenter retrospective study analyzing the prognostic impact of age according to treatment delivered in TN and Her2-positive BC patients of 70 years or older, including comparison by age groups.MethodsThe medical records of 31,473 patients treated from January 1991 to December 2018 were retrieved from 13 French cancer centers for retrospective analysis. Our study population included all ≥70 patients with TN or Her2-positive BC treated by upfront surgery. Three age categories were determined: 70-74, 75-80, and > 80 years.ResultsOf 528 patients included, 243 patients were 70-74 years old (46%), 172 were 75-80 years (32.6%) and 113 were >80 years (21.4%). Half the population (51.9%, 274 patients) were TN, 30.1% (159) Her2-positive/hormone receptors (HR)-positive, and, 18% (95) Her2-positive/endocrine receptors (ER)-negative BC. Advanced tumor stage was associated with older age but no other prognostic factors (tumor subtype, tumor grade, LVI). Adjuvant chemotherapy delivery was inversely proportional to age. With 49 months median follow-up, all patient outcomes (overall survival (OS), disease-free survival (DFS), breast cancer-specific survival (BCSS), and recurrence-free survival (RFS)) significantly decreased as age increased. In multivariate analysis, age >80, pT2-3 sizes, axillary macrometastases, lymphovascular involvement, and HR-negativity tumor negatively affected DFS and OS. Comparison between age >80 and 80 (HR=1.771, p=0.031).ConclusionTN and Her2-positive subtypes occur at similar frequency in elderly patients. Older age is associated with more advanced tumor stage presentation. Chemotherapy use decreases with older age without worse other pejorative prognostic factors. Age >80, but not ≤80, independently affected DFS and OS.

Background: There is a scarcity of data exploring early breast cancer (eBC) in very young patients. We assessed shared and intrinsic prognostic factors in a large cohort of patients aged ≤35, compared to a control group aged 36 to 50. Methods: Patients ≤50 were retrospectively identified from a multicentric cohort of 23,134 eBC patients who underwent primary surgery between 1990 and 2014. Multivariate Cox analyses for DFS and OS were built. To assess the independent impact of age, 1 to 3 case-control analysis was performed by matching ≤35 and 36–50 years patients. Results: Of 6481 patients, 556 were aged ≤35, and 5925 from 36 to 50. Age ≤35 was associated with larger tumors, higher grade, ER-negativity, macroscopic lymph node involvement (pN + macro), lymphovascular invasion (LVI), mastectomy, and chemotherapy (CT) use. In multivariate analysis, age ≤35 was associated with worse DFS [HR 1.56, 95% CI 1.32–1.84; p

Abstract Background Soft tissue sarcomas (STS) are heterogeneous and pro-metastatic tumors. Identification of accurate prognostic factors and novel therapeutic targets are crucial. CSPG4 is a cell surface proteoglycan with oncogenic functions. It recently emerged as a potential target for immunotherapy, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in STS. However, expression of CSPG4 is poorly known in STS so far. Methods We analyzed CSPG4 gene expression in 1378 localized STS clinical samples, and searched for correlations with clinicopathological data, including disease-free survival (DFS), and with tumor immune features. Results CSPG4 expression was heterogeneous across samples. High expression was associated with younger patients’ age, more frequent undifferentiated pleomorphic sarcoma and myxofibrosarcoma pathological subtypes, more frequent internal trunk tumor site, and more CINSARC high-risk samples. No correlation existed with pathological tumor size and grade, and tumor depth. Patients with high CSPG4 expression displayed 49% (95% CI 42–57) 5-year DFS versus 61% (95% CI 56–68) in patients with low expression (p = 3.17E−03), representing a 49% increased risk of event in the “CSPG4-high” group (HR = 1.49, 95% CI 1.14–1.94). This unfavorable prognostic value persisted in multivariate analysis, independently from other variables. There were significant differences in immune variables between “CSPG4-high” and “CSPG4-low” tumors. The "CSPG4-low" tumors displayed profiles suggesting higher anti-tumor cytotoxic immune response and higher potential vulnerability to immune checkpoint inhibitors (ICI). By contrast, the "CSPG4-high" tumors displayed profiles implying an immune-excluded tumor microenvironment, potentially induced by hypoxia, resulting from an immature chaotic microvasculature, and/or the presence of contractile myofibroblasts. Conclusions Patients with “CSPG4-high” STS, theoretically candidate for CAR.CIKs, display shorter DFS and an immune environment unfavorable to vulnerability to CAR.CIKs, which could be improved by combining anti-angiogenic drugs able to normalize the tumor vasculature. By contrast, “CSPG4-low” STS are better candidates for immune therapy involving ICI.

Abstract In some types of cancer, telomere length is maintained by the alternative lengthening of telomeres (ALT) mechanism. In many ALT cancers, the α‐thalassemia/mental retardation syndrome X‐linked (ATRX) gene is mutated leading to the conclusion that the ATRX complex represses ALT. Here, we report that most high‐grade pediatric osteosarcomas maintain their telomeres by ALT, and that the majority of these ALT tumors are ATRX wild‐type (wt) and instead carry an amplified 17p11.2 chromosomal region containing TOP3A. We found that TOP3A was overexpressed in the ALT‐positive ATRX‐wt tumors consistent with its amplification. We demonstrated the functional significance of these results by showing that TOP3A overexpression in ALT cancer cells countered ATRX‐mediated ALT inhibition and that TOP3A knockdown disrupted the ALT phenotype in ATRX‐wt cells. Moreover, we report that TOP3A is required for proper BLM localization and promotes ALT DNA synthesis in ALT cell lines. Collectively, our results identify TOP3A as a major ALT player and potential therapeutic target.

Stereotactic body radiotherapy (SBRT) and percutaneous thermal ablation (TA) are alternatives to surgery for the management of pulmonary oligometastases. In this collaborative work, we retrospectively analyzed patients who had undergone iterative focal ablative treatments of pulmonary oligometastases. We hypothesized that repeated ablative therapies could benefit patients with consecutive oligometastatic relapses. Patients treated with SBRT and/or TA for pulmonary oligometastases in two French academic centers between October 2011 and November 2016 were included. A total of 102 patients with 198 lesions were included; 45 patients (44.1%) received repeated focal treatments at the pulmonary site for an oligorecurrent disease (the “multiple courses” group). Median follow-up was 22.5 months. The 3-year overall survival rates of patients who had a single treatment sequence (the “single course” group) versus the “multiple courses” were 73.9% and 78.8%, respectively, which was not a statistically significant difference (p = 0.860). The 3-year systemic therapy-free survival tended to be longer in the “multiple courses” group (50.4%) than in the “single course” group (44.7%) (p = 0.081). Tolerance of repeated treatments was excellent with only one grade 4 toxicity. Thereby, multimodality repeated ablative therapy is effective in patients with pulmonary oligorecurrent metastases. This strategy may delay the use of more toxic systemic therapy.

Endometrioid ovarian cancers (EOvC) are usually managed as serous tumors. In this study, we conducted a comprehensive molecular investigation to uncover the distinct biological characteristics of EOvC. This retrospective multicenter study involved patients from three European centers. We collected clinical data and formalin‐fixed paraffin‐embedded (FFPE) samples for analysis at the DNA level using panel‐based next‐generation sequencing and array‐comparative genomic hybridization. Additionally, we examined mRNA expression using NanoString nCounter® and protein expression through tissue microarray. We compared EOvC with other ovarian subtypes and uterine endometrioid tumors. Furthermore, we assessed the impact of molecular alterations on patient outcomes, including progression‐free survival (PFS) and overall survival (OS). Preliminary analysis of clinical data from 668 patients, including 86 (12.9%) EOvC, revealed more favorable prognosis for EOvC compared with serous ovarian carcinoma (5‐year OS of 60% versus 45%; P = 0.001) driven by diagnosis at an earlier stage. Immunohistochemistry and copy number alteration (CNA) profiles of 43 cases with clinical data and FFPE samples available indicated that EOvC protein expression and CNA profiles were more similar to endometrioid endometrial tumors than to serous ovarian carcinomas. EOvC exhibited specific alterations, such as lower rates of PTEN loss, mutations in DNA repair genes, and P53 abnormalities. Survival analysis showed that patients with tumors harboring loss of PTEN expression had worse outcomes (median PFS 19.6 months vs. not reached; P = 0.034). Gene expression profile analysis confirmed that EOvC differed from serous tumors. However, comparison to other rare subtypes of ovarian cancer suggested that the EOvC transcriptomic profile was close to that of ovarian clear cell carcinoma. Downregulation of genes involved in the PI3K pathway and DNA methylation was observed in EOvC. In conclusion, EOvC represents a distinct biological entity and should be regarded as such in the development of specific clinical approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: Improved outcomes have been reported with adjuvant treatment combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy, in high-risk patients with ER-positive and HER2-negative breast cancer, regardless of age. In this real-world data analysis, MonarchE and NataLEE high-risk patients accounted for 9.5% and 33% of patients undergoing upfront surgery, respectively. Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. A higher discontinuation rate for abemaciclib was reported in patients ≥65 years and it can be assumed that discontinuation rates may increase with more older patients. If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population. Background: Despite early diagnosis, approximately 20% of patients with ER-positive and HER2-negative breast cancer (BC) will experience disease recurrence. Improved survival has been reported with adjuvant treatment combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy, in high-risk patients with ER-positive and HER2-negative BC, regardless of age. Older patients have higher rates of ER-positive/HER2-negative BC than younger patients. Methods: In this real-world data analysis, MonarchE and NataLEE high-risk patients accounted for 9.5% and 33% of patients undergoing upfront surgery, respectively. Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. Results: Eligibility rates in patients ≤40 years and >80 years who underwent mastectomy were 27.8% and 24.7% for abemaciclib, respectively, and 56.6% and 65.2% for ribociclib, respectively. A higher discontinuation rate for abemaciclib was reported in patients aged ≥65 years and it can be assumed that discontinuation rates may increase in even older patients. Conclusions: If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population. [ABSTRACT FROM AUTHOR]

Background: LIV1 is a transmembrane protein that may become a new therapeutic target through the development of antibody–drug conjugates (ADCs). Few studies are available regarding the assessment of LIV1 expression in clinical breast cancer (BC) samples. Methods: We analyzed LIV1 mRNA expression in 8982 primary BC. We searched for correlations between LIV1 expression and clinicopathological data, including disease-free survival (DFS), overall survival (OS), pathological complete response to chemotherapy (pCR), and potential vulnerability and actionability to anti-cancer drugs used or under development in BC. Analyses were performed in the whole population and each molecular subtype separately. Results: LIV1 expression was associated with good-prognosis features and with longer DFS and OS in multivariate analysis. However, patients with high LIV1 expression displayed a lower pCR rate than patients with low expression after anthracycline-based neoadjuvant chemotherapy, including in multivariate analysis adjusted on grade and molecular subtypes. LIV1-high tumors were associated with higher probabilities of sensitivity to hormone therapy and CDK4/6 inhibitors and lower probabilities of sensitivity to immune-checkpoint inhibitors and PARP inhibitors. These observations were different according to the molecular subtypes when analyzed separately. Conclusions: These results may provide novel insights into the clinical development and use of LIV1-targeted ADCs by identifying prognostic and predictive value of LIV1 expression in each molecular subtype and associated vulnerability to other systemic therapies.

Simple Summary: Omission of completion axillary lymph node dissection (cALND) in patients undergoing mastectomy with sentinel node (SN) isolated tumor cells (ITC) or micrometastases is discussed. We evaluated the impact of cALND omission on survival in breast cancer (BC) patients treated by mastectomy with SN ITC or micrometastases. Among 554 BC, the non-SN involvement rate was 13.2%. With a median follow-up of 66.46 months, multivariate analysis showed that cALND omission was significantly associated with overall survival (OS, HR: 2.583, p = 0.043), disease-free survival (DFS, HR: 2.538, p = 0.008), and metastasis-free survival (MFS, HR: 2.756, p = 0.014). For Her2-positive or triple-negative patients, DFS was significantly impacted by cALND omission (HR: 38.451, p = 0.030). In ER-positive Her2-negative patients, DFS, OS, RFS, and MFS were also significantly affected (HR: 2.358, 3.317, 2.538, 2.756). For 161 patients ≤ 50 years with ER-positive/Her2-negative BC, OS and BCSS were notably associated with cALND omission (HR: 103.47 and 50.874). These findings suggest a negative prognostic impact of cALND omission in patients with SN micrometastases or ITC. Omission of completion axillary lymph node dissection (cALND) in patients undergoing mastectomy with sentinel node (SN) isolated tumor cells (ITC) or micrometastases is debated due to potential under-treatment, with non-sentinel node (NSN) involvement detected in 7% to 18% of patients. This study evaluated the survival impact of cALND omission in a cohort of breast cancer (BC) patients treated by mastectomy with SN ITC or micrometastases. Among 554 early BC patients (391 pN1mi, 163 ITC), the NSN involvement rate was 13.2% (49/371). With a median follow-up of 66.46 months, multivariate analysis revealed significant associations between cALND omission and overall survival (OS, HR: 2.583, p = 0.043), disease-free survival (DFS, HR: 2.538, p = 0.008), and metastasis-free survival (MFS, HR: 2.756, p = 0.014). For Her2-positive or triple-negative patients, DFS was significantly affected by cALND omission (HR: 38.451, p = 0.030). In ER-positive Her2-negative BC, DFS, OS, recurrence-free survival (RFS), and MFS were significantly associated with cALND omission (DFS HR: 2.358, p = 0.043; OS HR: 3.317; RFS HR: 2.538; MFS HR: 2.756). For 161 patients aged ≤50 years with ER-positive/Her2-negative cancer, OS and breast cancer-specific survival (BCSS) were notably impacted by cALND omission (OS HR: 103.47, p = 0.004; BCSS HR: 50.874, p = 0.035). These findings suggest a potential negative prognostic impact of cALND omission in patients with SN micrometastases or ITC. Further randomized trials are needed. [ABSTRACT FROM AUTHOR]

The development of effective drug delivery systems is one of the major challenges in the fight against cancer. Gold nanoparticles could effectively harness cancer therapies by improving their potency while reducing toxic side effects. In this work, we describe a high-yield one-step synthesis of small water-soluble gold nanoparticles (AuNPs). Efficient purification was monitored, and discrete structure was fully characterized by combining molecular analytical technics (UV-visible and NMR spectroscopies) and solid-state analyses (thermal gravimetric analysis and transmission electron microscopy). These AuNPs have good dispersibility in various biocompatible media and can be used without any additives. Preliminary study with in vitro treatment of IB115 human cancer cells showed massive cellular uptake associated to moderate intrinsic cytotoxicity. The high control of the synthesis and the small size of these AuNPs are offering fine surface properties control, crucial for challenging biological nano-dispersion issues. Thus, limitation of the agglomeration of nanoparticles and improvement of interaction with the surface of cell should open new leads for vectorization of drugs or imaging probes for diagnosis.

Abstract Background For the year 2018, the French government plans a revision of bioethics laws, including certainly the recent Claeys-Leonetti law introducing the right to deep and continuous sedation at the request of palliative patients and prohibiting euthanasia for end-of-life patients. Because there is no published data on medical staff opposition to a deep and continuous palliative sedation request under Claeys-Leonetti law, we believe this report may give insight into physicians’ decision making, into the role of criteria for prudent practice, and thus contribute to the bioethical debate. Case presentation We report a 70-year-old patient with squamous cell carcinoma of the hypopharyngeal region, who categorically refused any treatment since one year and asked for deep and continuous palliative sedation until death after attempting suicide. The patient’s request was examined and denied by palliative multidisciplinary board, in accordance with by the French Oncology Coordination Centre guidelines. This situation did not fulfil the criteria requested by Claeys-Leonetti law. Conclusions As highlighted by the present case-report, patient’s expectation regarding palliative sedation can be ambivalent with properly so called euthanasia or assisted suicide. This ambivalent perception was part of the controversy surrounding the parliamentary debate, which is still relevant. This case report supports that deep and continuous sedation under Claeys-Leonetti law need to meet specific criteria defined by the law and documented in the medical files as a safeguard against inappropriate practice. In fact, one of the shortcomings of the current arrangements of Claeys-Leonetti law is a lack of objective medical-based criteria. So it is necessary that scientific peer-reviews papers be published quickly in order to deepen the bioethical debate on the end of life.

Abstract Background Opinion about euthanasia has been explored among the general population and recently in patients receiving palliative care. 96% of the French population declared themselves in favor of euthanasia while less of 50% of palliative care patients are. The aim of the present study was to explore and identify potential determinant factors associated with favorable or unfavorable opinion about euthanasia in a French population of cancer patients receiving palliative care. Methods We performed a cross-sectional study among patients in two palliative care units. Eligible patients were identified by the medical staff. Face-to-face interviews were performed by two investigators. Two groups were defined as favorable or unfavorable about euthanasia according to the answer on the specific question about patient opinion on euthanasia. A multivariate analysis including age, belief in God, chemotherapy and gender was built. Results Seventy-eight patients were interviewed. Median age was 60.5 years (range: 31–87.2). In univariate analysis, patients with a favorable opinion were most often under 60 years old (62 versus 38% unfavorable; p = 0.035), in couple (64 versus 35%; p = 0.032), didn’t believe in God (72 versus 28% were non-believers; p

Abstract Background Enhanced Recovery After Surgery Programs (ERP) includes multimodal approaches of perioperative patient’s clinical pathways designed to achieve early recovery after surgery and a decreased length of hospital stay (LOS). Methods This observational study evaluated the implementation of ERP in gynaecologic oncological surgery in a minimally invasive techniques (MIT) expert center with more than 85% of procedures done with MIT. We compared a prospective cohort of 100 patients involved in ERP between December 2015 and June 2016 to a 100 patients control group, without ERP, previously managed in the same center between April 2015 and November 2015. All the included patients were referred for hysterectomy and/or pelvic or para-aortic lymphadenectomy for gynaecological cancer. The primary objective was to achieve a significant decrease of median LOS in the ERP group. Secondary objectives were decreases in proportion of patients achieving target LOS (2 days), morbidity and readmissions. Results Except a disparity in oncological indications with a higher proportion of endometrial cancer in the group with ERP vs. the group without ERP (42% vs. 22%; p = 0.003), there were no differences in patient’s characteristics and surgical procedures. ERP were associated with decreases of median LOS (2.5 [0 to 11] days vs. 3 [1 to 14] days; p = 0.002) and proportion of discharged patient at target LOS (45% vs. 24%; p = 0.002). Morbidities occurred in 25% and 26% in the groups with and without ERP and readmission rates were respectively of 6% and 8%, without any significant difference. Conclusion ERP in gynaecologic oncological surgery is associated with a decrease of LOS without increases of morbidity or readmission rates, even in a center with a high proportion of MIT. Although it is already widely accepted that MIT improves early recovery, our study shows that the addition of ERP’s clinical pathways improve surgical outcomes and patient care management.