Nouvelles stratégies thérapeutiques dans les cancers du sein HER2-surexprimé: New therapeutic strategies in HER2-positive breast cancer.

Breast cancer with HER2-amplification accounts for 20 % of breast cancers. The management of patients has dramatically changed with the advent of anti-HER2 treatment, especially the monoclonal antibodies since 2000 in the metastatic and (neo)-adjuvant setting, leading to an improvement of patient outcomes. If therapeutic arsenal has been gradually enhanced with the targeting of HER receptors family, resistances to these treatments are observed, hence the development of new therapeutic strategies. This review provides an updated look of novel therapeutic strategies in HER2-positive breast cancer, as well as future perspectives, both in the adjuvant and metastatic setting.

[New therapeutic strategies in HER2-positive breast cancer]. / Nouvelles stratégies thérapeutiques dans les cancers du sein HER2-surexprimé.

Breast cancer with HER2-amplification accounts for 20% of breast cancers. The management of patients has dramatically changed with the advent of anti-HER2 treatment, especially the monoclonal antibodies since 2000 in the metastatic and (neo)-adjuvant setting, leading to an improvement of patient outcomes. If therapeutic arsenal has been gradually enhanced with the targeting of HER receptors family, resistances to these treatments are observed, hence the development of new therapeutic strategies. This review provides an updated look of novel therapeutic strategies in HER2-positive breast cancer, as well as future perspectives, both in the adjuvant and metastatic setting.

Synchronous brain metastases as a poor prognosis factor in clear cell renal carcinoma: a strong argument for systematic brain screening.

PURPOSE: Brain metastases (BM) usually represent a poor prognostic factor in solid tumors. About 10% of patients with renal cancer (RCC) will present BM. Local therapies such as stereotactic radiotherapy (SRT), whole brain radiotherapy (WBRT), and surgery are used to achieve brain control. We compared survival between patients with synchronous BM (SynBM group) and metachronous BM (MetaBM group). METHODS: It is a retrospective study of patients with clear cell renal cell carcinoma (ccRCC) and BM treated with TKI between 2005 and 2019 at the Centre Léon Bérard in Lyon. We collected prognostic factors: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, the TNM stage, the histological subtypes and the Fuhrman grade. Overall survival (OS) was defined from diagnosis of metastatic ccRCC to death. Brain progression-free survival (B-PFS) was defined from focal brain therapy to brain progression or death. RESULTS: 99 patients were analyzed, 44 in the SynBM group and 55 in the MetaBM group. OS in the MetaBM group was 49.4 months versus 19.6 months in the SynBM group, p = 0.0002. The median time from diagnosis of metastasic disease to apparition of BM in the MetaBM group was 22.9 months (4.3; 125.7). SRT was used for 101 lesions (66.4%), WBRT for 25 patients (16.4%), surgery for 21 lesions (13.8%), surgery followed by radiation for 5 lesions (3.3%). B-PFS for all patients was 7 months (IC95% [5.0-10.5]). CONCLUSIONS: Survival of patients with synchronous BM is inferior to that of patients with metachronous BM. Outcome is poor in both cases after diagnosis of BM. Brain screening should be encouraged at time of diagnosis of metastatis in ccRCC.

Poly(ADP-ribose) polymerase inhibitors in combination with anti-angiogenic agents for the treatment of advanced ovarian cancer.

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.

Lay abstract Ovarian cancers often present difficulties to repair their DNA and are highly vascularized tumors. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. They use one type of therapy to target the difficulty of ovarian cancer to repair their DNA which is called poly(ADP-ribose) polymerase inhibitor. This type of therapy has become standard of care after chemotherapy. In this review, we discuss the advantage of combining anti-angiogenic agents to poly(ADP-ribose) polymerase inhibitors to target the fact that tumors are highly vascularized. First, data from laboratory suggest synergistic activity of the combination. Then, clinical data are also in favor of the combination due to additive efficacy, and a good safety and cost-effective profile.

Molecular Classification of Endometrial Stromal Sarcomas Using RNA Sequencing Defines Nosological and Prognostic Subgroups with Different Natural History.

A series of 42 patient tumors diagnosed as endometrial stromal sarcoma (ESS) based on the morphology but negative for JAZF1 and/or YWHAE rearrangement in FISH was analyzed by RNA-sequencing. A chromosomal rearrangement was identified in 31 (74%) of the cases and a missense mutation in known oncogenes/tumor suppressor genes in 11 (26%). Cluster analyses on the expression profiles from this series together with a control cohort composed of five samples of low grade ESS harboring a JAZF1-SUZ12 fusion, one high grade ESS harboring a BCOR-ITD, two uterine tumors resembling ovarian sex cord tumors, two samples each of uterine leiomyoma and leiomyosarcomas and a series of BCOR-rearranged family of tumor (n = 8) indicated that tumors could be gather in three distinct subgroups: one mainly composed of BCOR-rearranged samples that contained seven ESS samples, one mainly composed of JAZF1-fused ESS (n = 15) and the last composed of various molecular subtypes (n = 19). These three subgroups display different gene signatures, different in silico cell cycle scores and very different clinical presentations, natural history and survival (log-rank test, p = 0.004). While YWHAE-NUTM2 fusion genes may be present in both high and low grade ESS, the high-grade presents with additional BCOR or BCORL1 gene mutations. RNAseq brings clinically relevant molecular classification, enabling the reclassification of diseases and the guidance of therapeutic strategy.

[Intensification by high dose chemotherapy for germ-cell tumors, still an ongoing subject?] / État des lieux de la chimiothérapie intensive avec support de cellules-souches hématopoïétiques dans le traitement des tumeurs germinales.

More than 80 % of patient with metastatic germ cell tumor are cured with first line chemotherapy. Twenty to 30 % of patients will experience relapse or refractory disease with a very poor long-term prognosis. Most of them had metastatic germ cell tumors with a poor prognosis according to the international germ cell classification collaborative group (IGCCCG). The role of treatment intensification by high dose chemotherapy (HDCT) followed by stem cell rescue has not been demonstrated yet in the first line setting compared to standard chemotherapy. The role of HDCT in first or second salvage is also not yet demonstrated, many studies have been published in this situation with a lot of different regimen. Outside clinical trial, HDCT remains an option in salvage therapy, depending on many factors including prognostics factors, previous therapy, general condition and reference center consideration to select eligible patient who could benefit the most of this approach. Results from the international randomized trial TIGER will provide evidence-based information for HDCT strategy.

[Treatment of testicular germ cell tumors relapse]. / Actualités dans le traitement à la rechute des patients atteints de tumeurs germinales.

Seminomatous (SGCT) and non-seminomatous (NSGCT) germ cell tumors (GCT) are rare but their incidence are increasing. We will discuss different therapeutic strategies in relapse disease: patients with stage I germ cell tumor have an excellent prognosis with a cure rate approaching 98-99 %, whatever the histology and the chosen treatment (surveillance strategy or adjuvant treatment). Relapses are observed among 20% of patients with stage I SGCT or low risk NSGCT and 50 % of patients with high risk NSGCT. Patients are treated according to the international prognosis group (IGCCCG) for SGCT and low risk NSGCT, naïve of chemotherapy. After an adjuvant treatment, the protocol must be adapted to the number of previous cycles (1 or 2 BEP) and to the prognosis group. Five to 50% of patients relapse after a first line of metastatic chemotherapy according to initial prognosis group. Dose-dense chemotherapy according to the GETUG13 protocol reduces the risk of relapse for the patients with poor-risk group NSGCT and unfavorable tumor marker decline. The prognosis of patients with relapsed or refractory GCT after a first line is more negative since only half of them will be cured by salvage standard chemotherapy. An international therapeutic trial (TIGER) is ongoing in first line salvage treatment evaluating high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation (HSCT). Finally, developing biomarkers for predicting clinical relapse, the management in expert centers of these patients and participation in therapeutic innovation are important perspectives for a better understanding and treatment of these patients with a poorer prognosis.

Very long-term survivors among patients with metastatic soft tissue sarcoma.

BACKGROUND: Metastatic soft tissue sarcomas (STS) are a group of rare and heterogeneous mesenchymal tumors with a poor prognosis. The aim of this study was to evaluate the incidence of long-term survivors and describe their presentation and management in a large cohort of patients with metastatic STS. METHODS: We collected information of patients with metastatic STS managed in Centre Leon Berard between 1985 and 2015 aiming to compare the group of patients alive 5 years after the diagnosis of metastases vs the others. Prognostic factors of patients and tumors characteristics were investigated by logistic regression analysis. For "long-term survivors," we explored therapeutic strategies at metastatic stage. RESULTS: Out of 436 patients enrolled, 39 (9%) were still alive 5 years after diagnostic of metastases with a median survival of 146 months (12 years). This "long-term survivors" group included more female and younger patients, with better performance status, more synovial sarcoma or endometrial stromal sarcoma, more patients with simple genomic sarcomas, lower tumor grade, smaller tumor, and longer disease-free interval. In multivariate analysis, age below 55 at metastatic stage (P = 0.0002) and grade 1 tumor (P < 0.0001) were significantly associated with the "long-term survivors." Their therapeutic management was usually aggressive (intensified or polychemotherapy, repeated local treatment of metastases), leading to 62% of complete response in first-line setting. CONCLUSIONS: Very long-term survivors are observed in metastatic STS. Selection of patients in good condition with less aggressive tumor and administration of intensive treatment may lead to obtain these motivating results in a poor prognosis disease.

Inequalities in lung cancer: a world of EGFR.

Epidermal growth factor receptor gene (EGFR) mutation status has emerged as a crucial issue in lung cancer management. Availability and cost of tests and tyrosine kinase inhibitors (TKIs) may vary as a function of country development.We conducted a prospective specialist opinion survey to map EGFR test and EGFR-TKI availability and detect associations with the Human Development Index (HDI). A questionnaire was sent to specialists in thoracic oncology in all United Nations Member States.We obtained responses from 74 countries, comprising 78% of the worldwide population. Nonresponding countries had significantly lower HDI rank than responding countries. EGFR mutation analysis was routinely available in 57 countries (70% of the worldwide population). The cost of the test was

Lung cancer may increase serum procalcitonin level.

INTRODUCTION: Serum procalcitonin (PCT) is a biomarker used routinely to diagnose infections. Some malignancies are usual false positives for PCT. However, its value and behavior in the setting of lung cancers are poorly known. The objective of this study was to assess PCT positivity in a lung cancer cases series. METHOD: Between November 2011 and September 2012, all cases of newly diagnosed lung cancer with a pre-antineoplastic PCT assay and no patent signs of infection were included in the study. All PCT levels were assessed by immunofluorescent assay in a single laboratory. RESULTS: Eighty-nine patients were included (70.8% male; mean age 62; small-cell cancer 20.2%; stage IV cancer 60.7%). Overall, PCT was positive in 42%. A neuroendocrine component, having 2 or more metastatic sites, having a pleura or a liver metastasis, and being positive for CRP were all significantly associated with positive PCT in univariate analysis. In multivariate analysis, only the presence of a neuroendocrine component remained strongly associated with a positive PCT (AOR=7.24 [CI=95% 1.91-27.51]; P=0.004). Finally, baseline PCT levels <0.5 µg/l were found in 43% of NSCLC with a neuroendocrine component, vs. 9% of cancers with other histology (P=0.0001). CONCLUSION: Lung cancer may cause false positives for procalcitonin, particularly in cases of neuroendocrine cancers or in the presence of multiple metastases. These results should be taken into account for PCT-based decisional algorithms.

Pneumocystis jirovecii pneumonia under everolimus in two patients with metastatic pancreatic neuroendocrine tumors.

BACKGROUND: Everolimus, an mTOR inhibitor with immunosuppressive properties, is used in several types of advanced tumors. Materials and METHODS: We describe the first two cases of Pneumocystis jirovecii pneumonia in patients given everolimus for metastatic pancreatic neuroendocrine tumors. RESULTS: The first patient presented with respiratory symptoms in the context of grade 4 lymphopenia 2 weeks after starting everolimus; the diagnosis of Pneumocystis jirovecii pneumonia was made post-mortem. After suspecting everolimus-related interstitial pneumonitis in the second patient, Pneumocystis jirovecii was detected, and cotrimoxazole therapy led to a favorable outcome. CONCLUSION: Everolimus may induce pneumonitis, lymphopenia and opportunistic infections. The time from treatment initiation to opportunistic infection may be short. Risk factors in oncology deserve further identification in order to start prophylaxis without delay.