Mutational Profile of Malignant Pleural Mesothelioma (MPM) in the Phase II RAMES Study.

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive cancer. Data are not available in prospective trials on correlations between genetic alterations and outcomes of therapies. In this study, we assessed the genetic profile of MPM patients (pts) in tissue samples. Patients and Methods: From December 2016 to July 2018 (end of enrolment), 164 pts were enrolled. We evaluated by targeted sequencing the mutational profile of a panel of 34 genes: ACTB, ACTG1, ACTG2, ACTR1A, BAP1, CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53, TXNRD1, UQCRC1, XRCC6. Genetic profiling was correlated with clinical and pathological variables. Results: Overall, 110 pts (67%) from both treatment arms had samples available for molecular analysis. Median age was 63 years (45-81), 25.5% (n = 28) were females, and 74.5% (n = 82) were males. Tumor histotype was 81.8% (n = 90) epithelioid and 18.2% (n = 20) non-epithelioid; 28.5% of the tumors (n = 42) were stage IV, 71.5% (n = 68) were stage III. Targeted sequencing of tissue specimens identified 275 functional somatic mutations in the 34 genes analyzed. The number of mutated genes was positively associated with higher stage and metastatic disease (p = 0.025). RDX (42%), MXRA5 (23%), BAP1 (14%), and NF2 (11%) were the most frequently mutated genes. Mutations in RAPGEF6 (p = 0.03) and ACTG1 (p = 0.02) were associated with the non-epithelioid subtype, and mutations in BAP1 (p = 0.04) were related to progression-free survival (PFS) > 6 months. Conclusions: In the Ramucirumab Mesothelioma clinical trial (RAMES), mutation of the gene BAP1 is related to a prolonged PFS for patients treated with platinum/pemetrexed regimens (p = 0.04).

Pei regimen: a therapeutic option in small cell lung cancer? A retrospective monoinstitutional analysis of 46 consecutive cases.

OBJECTIVES: Combination chemotherapy is very active in small cell lung cancer (SCLC), although no improvement in overall survival (OS) has been done in the last 25 years, with Cisplatin-Etoposide (PE) still considered the world-wide standard, with an average median survival of about 7-8 months in patients with extended disease (ED). In 1995, a randomized trial of the Hoosier Group in 171 ED patients showed a significant advantage in overall survival in patients treated with PEI (Cisplatin, Etoposide and Ifosfamide), compared to PE. Despite that, PEI regimen has not become a commonly used regimen in SCLC. MATERIALS AND METHODS: Here we present a retrospective analysis of 46 consecutive patients (30 males and 16 females) with SCLC that were treated at our Institution with PEI regimen: Cisplatin 20 mg/m2, Etoposide 75 mg/m2 and Ifosfamide 1200 mg/m2, day 1 to 4, every 3 weeks. Patients received a total of 219 cycles of chemotherapy, with a mean of 4,7 cycles per patient. Median age was 63 (range 59-70); performance status (PS) was 0 in 29 patients (63%), 1 in 13 patients (28%) and 2 in 4 patients (9%). RESULTS: In 19 limited disease (LD) patients partial response (PR) rate was 74%, and complete response (CR) was 16%. In 27 ED patients we observed 63% of PR and 26% of CR. Median time to progression (TTP) was 15.2 months in LD and 7.1 months in ED with median overall survival (OS) of 28.2 and 11.8 months, respectively. Toxicity was manageable, with a high dose intensity. CONCLUSIONS: PEI regimen, in our opinion, may be a possible therapeutic option, with high activity and an acceptable toxicity profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02324296 . INSTITUTIONAL REVIEW BOARD THAT APPROVED THE STUDY: Institutional review board of Reggio Emilia, Azienda Ospedaliera S.Maria Nuova/IRCCS.

A case of necrotizing vasculitis with panniculitis, during sorafenib treatment for hepatocellular carcinoma, appeared in disease progression.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and is the third most common cause of death from cancer. Sorafenib is the only drug which improves survival in first line advanced HCC. Sorafenib has been associated with several dermatologic toxicities and toxic effects have been related to a better treatment response. We report the case of a well-circumscribed panniculitis and necrotizing vasculitis due to sorafenib, appeared in disease progression in a man affected by advanced HCC.

Sorafenib efficacy in thymic carcinomas seems not to require c-KIT or PDGFR-alpha mutations.

PURPOSE: To retrospectively evaluate sorafenib activity and safety in patients with metastatic thymic carcinoma (TC) and to correlate outcome with c-KIT and PDGFR-alpha mutational status. PATIENTS AND METHODS: Patients with metastatic thymic carcinoma treated with sorafenib after at least one prior line of chemotherapy were included. Objective response rate (ORR) and toxicity were evaluated. Analysis of c-KIT and PDGFR-alpha mutational status was performed retrospectively. RESULTS: From October 2007 to August 2011, 5 patients with metastatic thymic carcinoma were evaluated. A median of 8 cycles of sorafenib (range=3-29) were administered. Two patients (40%) displayed a partial response (PR), two patients presented stable disease (SD), while one patient had progression. The median progression-free (PFS) and overall survival were 28 weeks and 92 weeks, respectively. At mutational analysis, only one patient with PR had c-KIT mutation in exon 17 and was successfully treated with sunitinib for 12 months after progression to sorafenib. No PDGFR-alpha mutations were found. CONCLUSION: Sorafenib activity seems independent from the c-KIT and PDGFR-alpha mutational status. After progression, sequence treatment with a different tyrosine kinase inhibitor can be considered. These results are promising and need further confirmation on larger, possibly prospective, series of patients.

Therapeutic activity of testosterone in metastatic breast cancer.

BACKGROUND: Hormone therapy plays an important role in the management of breast cancer. In the past, testosterone was the most common line of hormonal therapy for this disease, but its use has been almost completely abandoned in the past 40 years. However, because of earlier reports on favorable therapeutic results, we re-evaluated its use for treatment of hormone-responsive patients who have become refractory to other lines of hormonal therapy. PATIENTS AND METHODS: Fifty-three consecutive patients with positive metastatic breast cancer who had become refractory to treatment with other hormones and whose disease was progressing, were treated with testosterone propionate, 250 mg once every two weeks, twice, and then once every four weeks until disease progression, drug toxicity, or death. RESULTS: Regression of disease was seen in 9 patients (17%; 2% complete and 15% partial). Stabilization of disease was seen in 22 patients (41.5%). In the remaining 22 patients (41,5%), the disease progressed. Median overall survival was 12 months from beginning of testosterone treatment. Hirsutism and dysphonia were noted occasionally, but were not distressing enough to mandate cessation of treatment. There was no major toxicity except for two non-fatal pulmonary emboli. CONCLUSION: Testosterone showed a significant therapeutic activity in previously hormone-treated patients with metastatic breast cancer who were no longer responding to such treatment and whose disease was progressing. These results warrant consideration of testosterone use as treatment for patients with hormone-sensitive metastatic breast cancer.