Sporadic Metastatic Malignant Peripheral Nerve Sheath Tumour with an NF1 Mutation Responding to Trametinib: A Case Report.

Sporadically occurring malignant peripheral nerve sheath tumours (MPNSTs) can have a variety of genomic alterations including altered NF1, leading to activation of the RAS-RAF-MEK-ERK signalling pathway. Trametinib is an inhibitor of MEK1 and MEK2. Here we present a case of a patient diagnosed with sporadic MPNST with an identified NF1 gene treated successfully with trametinib.

Utility of a mainstreamed genetic testing pathway in breast and ovarian cancer patients during the COVID-19 pandemic.

INTRODUCTION: Mainstreamed genetic testing (MGT) obviates the need for a cancer genetics consultation, since trained oncologists (O) and gynaecologists (G) provide counseling, prescribe testing and deliver results. We report results from our MGT program and emphasize its utility during the COVID-19 lockdown, when cancer genetics clinics had suspended their activity. METHODS: An MGT pathway for breast and ovarian cancer (BC/OC) patients was established in Jan-2018 between the Assistance Publique - Hôpitaux de Paris.Sorbonne Université Cancer Genetics team and the Oncology/Gynecology departments at one teaching and two regional hospitals. Trained O + G evaluated patients with the Manchester Scoring System. A 12-point threshold was recommended for testing. Next-generation sequencing of BRCA1, BRCA2, PALB2, RAD51C and RAD51D was performed. Results were delivered to the patient by O/G. Pathogenic variants (PV) carriers were referred to the genetics clinic. Results are reported for the 2nd-Jan-2018 to 1st-June-2020 period. That includes the eight-week COVID-19 lockdown and three-week de-confinement phase 1. RESULTS: Results were available for 231/234 patients. Twenty-eight (12.1%) carried a PV. Of the 27 patients tested during the COVID-19 period, three carried a PV, two in BRCA1 and one in RAD51C. The clinical impact was immediate for the two BRCA1 BC cases undergoing neo-adjuvant chemotherapy, since double mastectomy and salpingo-oophorectomy will now be performed using two-step strategies. CONCLUSIONS: MGT guaranteed care continuity in BC/OC patients during the critical phases of the COVID-19 pandemic, with immediate implications for PV carriers. More broadly, we report for the first time the successful implementation of MGT in France.

Haematopoietic stem cell transplantation in adult soft-tissue sarcoma: an analysis from the European Society for Blood and Marrow Transplantation.

BACKGROUND: The role of high-dose chemotherapy with autologous stem cell transplantation (ASCT) in the treatment of soft-tissue sarcoma (STS) remains an unsettled issue. Prospective clinical trials failed to prove a benefit of the procedure but were limited by small and heterogeneous patient cohorts. Thus, it is unknown if ASCT may be a valuable treatment option in specific patient subgroups. METHODS: The purpose of this study was to investigate the value of ASCT according to histological subtype in STS patients who were registered in the European Society for Blood and Marrow Transplantation database between 1996 and 2016. RESULTS: Median progression-free (PFS) and overall survival (OS) in the entire cohort of 338 patients were 8.3 and 19.8 months, respectively, and PFS and OS at 5 years were 13% and 25%, respectively. Analysis of outcomes in different subgroups showed that younger age, better remission status before transplantation and melphalan-based preparative regimen were predictive of benefit from ASCT, whereas histology and grading had no statistically significant impact. CONCLUSIONS: Outcomes after ASCT compared favorably to those of recent trials on conventional chemotherapies and targeted therapies in STS, including histology-tailored approaches. ASCT, thus, should be reinvestigated in clinical trials focusing on defined patient subgroups.

Familial pancreatic adenocarcinoma: A retrospective analysis of germline genetic testing in a French multicentre cohort.

The rate of genetic diagnosis of French patients with familial pancreatic ductal adenocarcinoma (PDAC) is not known. We report germline genetic testing data from 133 index cases meeting criteria for familial pancreatic cancer (FPC) as well as 87 'FPC-like' index cases who did not fulfilled strict FPC definition but were evocative for a PDAC predisposition. The overall rate of genetic diagnosis (in BRCA1, BRCA2, CDKN2A, and ATM genes) was 8.3% in FPC patients and 4.6% in FPC-like patients, consistent with the literature in other populations. Genetic variants were also identified in FANCA and BAP1 genes, as well as in the CDKN2A p12 transcript. This pancreas-specific transcript is a known key player in driving pancreatic oncogenesis. This might be the first described case of a PDAC genetic predisposition due to a variant in this specific transcript.

Treatments, Outcomes, and Validity of Prognostic Scores in Patients With Sarcomatoid Renal Cell Carcinoma: A 20-Year Single-Institution Experience.

INTRODUCTION: Metastatic renal cell carcinoma (RCC) with a sarcomatoid component is a rare disease associated with a poor prognosis. We report the outcomes of 47 patients with metastatic sarcomatoid RCC (SRCC) treated with different modalities including chemotherapy, tyrosine kinase inhibitors, or immunotherapy over 2 decades in a French cancer center. Furthermore, we assessed the validity of prognostic scores in this subset of RCC. PATIENTS AND METHODS: Patients were retrospectively identified from the database of the pathology department of the University Hospital of Strasbourg. We enrolled all patients with RCC with a sarcomatoid component diagnosed between 1995 and 2016. Patients with nonmetastatic RCC were excluded. Recorded variables included: clinical stage, metastatic sites, pathologic stage, type of treatments, prognostic group, and survival data. The primary end point was overall survival. The institutional ethical committee approved the study protocol. RESULTS: Of 104 patients with SRCC, 47 patients with metastatic SRCC were included. The median age was 60 years (range, 41-77 years). Median length of follow-up was 34 months (range, 1-180 months). Fifty-five percent of patients had known metastases at diagnosis. Lung represented the first metastatic site (70%) followed by glandular (28%), bone (23%), liver (21%), and brain (6%). Fifteen percent of patients received immunotherapy including cytokine-based therapy (n = 7), or checkpoint inhibitors (n = 2). Moreover, 7 patients received chemotherapy. Five patients received no systemic treatment because of their poor performance status. Of 42 treated patients, 2 patients achieved complete response and 9 partial response (24%). Median overall survival was 13.3 months. International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups were valid in this subset of SRCC patients. A sarcomatoid percentage cutoff of 30% had the strongest influence on overall survival. CONCLUSION: Despite the arrival of tyrosine kinase inhibitors 10 years ago, metastatic SRCC remains a disease of poor prognosis and difficult to treat. Chemotherapy regimen and targeted therapies showed little activity in SRCC. IMDC score is a relevant prognostic factor in SRCC patients. Additionally, the MSKCC score, the sarcomatoid percentage, the necrotic fraction, and the vascular invasion could prove useful in identifying patients with a more favorable prognosis. These findings could help toward better patient stratification in clinical trials. Prospective trials assessing new drugs including immune checkpoint inhibitors are currently ongoing to improve SRCC survival.

Cetuximab-Carboplatin-5-Fluorouracil Regimen in Elderly Patients with Recurrent or Metastatic Head and Neck Squamous-Cell Carcinoma: A French Retrospective Survey.

BACKGROUND: The cetuximab plus platinum-based chemotherapy regimen is a standard of care in the treatment of recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The feasibility in the elderly population is currently unknown. METHODS: We performed a retrospective study in order to assess the efficacy and safety of the cetuximab plus platinum-based chemotherapy regimen in patients >65 years with recurrent or metastatic HNSCC. We performed a retrospective review of all medical records from recurrent or metastatic HNSCC patients >65 years treated with the cetuximab plus platinum-based chemotherapy regimen between September 2008 and December 2013 in our institution (Centre Paul Strauss, Strasbourg, France). RESULTS: A total of 59 patients were identified. Carboplatin in combination with 5-fluorouracil (FU) was the only cetuximab-associated chemotherapy regimen used for treating elderly patients. The median progression-free survival was 4 months (95% confidence interval [CI]: 2.9-4.7), and the median overall survival was 9.1 months (95% CI: 6.5-13.1). Grade 3 or 4 toxicity adverse events occurred in 52% (n = 31) of the patients (mostly hematologic toxicities and infections). CONCLUSIONS: This retrospective study suggests that the cetuximab plus carboplatin-5FU chemotherapy is an effective treatment option for elderly patients with recurrent or metastatic HNSCC.

"Hockey Stick" may Strike Back: Hepatocellular Carcinoma on Noncirrhotic Liver as a Late Toxicity of Lombo-Aortic Radiotherapy for Seminoma. A Review Triggered by an Unusual Case.

Most patients with testicular seminoma have been treated with a curative intent for decades. Second cancers after radiotherapy for testicular seminoma before 1990 are a growing issue, and are related to previous generation of dose planning and delineating strategies. Among those cancers, hepatocellular carcinoma is an extremely rare occurrence, especially when affecting patients with healthy, noncirrhotic liver. Here, we describe such a case in a patient of our institution, and subsequently review the relevant literature and large epidemiologic studies. Understanding those late and serious toxicity features may help cancer care teams to screen and treat those patients appropriately.

Prognostic factors in second-line targeted therapy for metastatic clear-cell renal cell carcinoma after progression on an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor.

BACKGROUND: About 40% of metastatic clear-cell renal cell carcinoma (m-ccRCC) patients receive a second-line targeted therapy after failure of anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGFR-TKI). Efficacy of second-line therapy is usually limited and prognostic and predictive factors at the start of second-line therapy are lacking. To identify the subgroup of patients that will benefit from such treatment remains a challenge. METHODS: We performed a multi-institutional, retrospective study of patients who received a second-line therapy after progression on an anti-VEGFR-TKI. Univariate and multivariate analyses were performed in order to identify prognostic factors for progressive disease (PD) as best response, progression-free survival (PFS) and overall survival (OS) on second-line therapy. RESULTS: For the whole cohort of 108 patients, mOS from the start of second-line therapy was 8.9 months while mPFS on second-line therapy was 2.8 months. A total of 49/105 (47%) patients had PD, 50/105 (48%) stable disease (SD) and 6/105 (6%) a partial response (PR). On multivariate analysis, the following markers were associated with improved outcome on second-line therapy: a PFS on first-line therapy ≥12 months (HR for PFS: 1.961; p = 0.008) (HR for OS: 1.724; p = 0.037) and Fuhrman grade 1-2 tumors (HR for OS: 2.198; p = 0.007). Markers associated with poorer outcome on second-line therapy were: elevated serum lactate dehydrogenase (LDH) levels (HR for PFS: 0.511; p = 0.04) (HR for OS: 0.392; p = 0.017), low albumin (HR for OS: 0.392; p = 0.01) and elevated corrected calcium levels (HR for OS: 0.416; p = 0.01). The impact on OS of the Memorial Sloan Kettering Cancer Centre (MSKCC) and International Renal Cell Carcinoma Database Consortium (IMDC) prognostic scores as calculated at start of second-line therapy was validated in our patient series. CONCLUSIONS: Duration of first-line PFS, Fuhrman grade, serum LDH levels, albumin levels, corrected calcium levels and the MSKCC and IMDC scores calculated at start of second-line therapy are prognostic factors for m-ccRCC patients treated with second-line targeted therapy.