Vincent Servois

Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.

BACKGROUND Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. METHODS The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patients tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physicians choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458. FINDINGS Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8-11·6) in the experimental group and 11·3 months (8·1-11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7-3·8) in the experimental group versus 2·0 months (1·8-2·1) in the control group (hazard ratio 0·88, 95% CI 0·65-1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3-4 adverse events (p=0·30). INTERPRETATION The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physicians choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy.

Surgical management of liver metastases from uveal melanoma: 16 years' experience at the Institut Curie

BACKGROUND Uveal melanoma is characterised by a high prevalence of liver metastases and a poor prognosis. AIM To review the evolving surgical management of this challenging condition at a single institution over a 16-year period. PATIENTS AND METHODS Between January 1991 and June 2007, among 3873 patients with uveal melanoma, 798 patients had liver metastases. We undertook a detailed retrospective review of their clinical records and surgical procedures. The data was evaluated with both uni- and multivariate statistical analysis for predictive survival indicators. RESULTS 255 patients underwent surgical resection. The median interval between ocular tumour diagnosis and liver surgery was 68 months (range 19-81). Liver surgery was either microscopically complete (R0; n = 76), microscopically incomplete (R1; n = 22) or macroscopically incomplete (R2; n = 157). The median overall postoperative survival was 14 months, but increased to 27 months when R0 resection was possible. With multivariate analysis, four variables were found to independently correlate with prolonged survival: an interval from primary tumour diagnosis to liver metastases >24 months, comprehensiveness of surgical resection (R0), number of metastases resected (< or = 4) and absence of miliary disease. CONCLUSIONS Surgical resection, when possible, is able to almost double the survival and appears at present the optimal way of improving the prognosis in metastatic uveal melanoma. Advances in medical treatments will be required to further improve survival.

Treatment of liver metastases from uveal melanoma by combined surgery—chemotherapy

AIMS To investigate sporadic results demonstrating prolonged survival after surgical resection and/or intraarterial chemotherapy (IACH) for liver metastases from uveal melanoma. METHODS From December 1992 to March 1997 every patient with liver metastases from uveal melanoma was enrolled in a prospective study including: (1) aggressive surgical approach removing as much liver disease as possible; (2) implantation of an intraaterial catheter; (3) intraarterial chemotherapy for 6 months. 75 patients were enrolled: 38 men, 37 women, mean age 51 years (range: 18-72), mean time from initial diagnosis of uveal melanoma to liver metastases 37 months (ranged: 1-168). RESULTS Disseminated disease in both lobes was present in all but one patient. Macroscopically curative surgery was possible in 27.5%. Significant tumour reduction was performed in 49.3% and a simple biopsy was possible in 23.2%. Eight patients did not receive chemotherapy and died soon after. IACH included Fotemustine and/or DTIC-Platinum for 4-9 cycles. Overall median survival was 9 months; very similar to non-operated historical controls. In the 61 patients receiving complete treatment surgery plus chemotherapy, median survival improved to 10 months. When curative resection was possible, survival increased to 22 months (P < 0.001). CONCLUSIONS Aggressive surgical resection, when possible, appears to be the best method of improving survival of liver metastases from uveal melanoma. New drug combinations are also required to improve survival.

Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma

Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ/GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation‐specific bidirectional pyrophosphorolysis‐activated polymerization (bi‐PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearch® technique. Patient characteristics and outcome were prospectively collected. CTCs (≥1) were detected in 12 of the 40 included patients (30%, range 1–20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4–11,421 copies/mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p = 0.004 and 0.03, respectively), with metastasis volume (p = 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression‐free survival (p = 0.003 and 0.001) and overall survival (p = 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value.

How to Boost the Breast Tumor Bed? A Multidisciplinary Approach in Eight Steps

PURPOSE To describe a new procedure for breast radiotherapy that will improve tumor bed localization and radiotherapy treatment using a multidisciplinary approach. PATIENTS AND METHODS This pilot study was conducted by departments of radiation oncology, surgery, and radiology. A new procedure has been implemented, summarized as eight steps: from pre-surgery contrast CT to surgery, tumor bed planning target volume (PTV) determination, and finally breast and tumor bed irradiation. RESULTS Twenty patients presenting with T1N0M0 tumors were enrolled in the study. All patients underwent lumpectomy with the placement of surgical clips in the tumor bed region. During surgery, 1 to 5 clips were placed in the lumpectomy cavity before the plastic procedure. All patients underwent pre- and postoperative CT scans in the treatment position. The two sets of images were registered with a match-point registration. All volumes were contoured and the results evaluated. The PTV included the clips region, the gross tumor volume, and the surgical scar, with an overall margin of 5-10 mm in all directions, corresponding to localization and setup uncertainties. For each patient the boost PTV was discussed and compared with our standard forward-planned PTV. CONCLUSIONS We demonstrate the feasibility of a tumor bed localization and treatment procedure that seems adaptable to routine practice. Our study shows the advantages of a multidisciplinary approach for tumor bed localization and treatment. The use of more than 1 clip associated with pre- to postoperative CT image registration allows better definition of the PTV boost volume.

Randomised proof-of-concept phase II trial comparing targeted therapy based on tumour molecular profiling vs conventional therapy in patients with refractory cancer: results of the feasibility part of the SHIVA trial

Background:The SHIVA trial is a multicentric randomised proof-of-concept phase II trial comparing molecularly targeted therapy based on tumour molecular profiling vs conventional therapy in patients with any type of refractory cancer. Results of the feasibility study on the first 100 enrolled patients are presented.Methods:Adult patients with any type of metastatic cancer who failed standard therapy were eligible for the study. The molecular profile was performed on a mandatory biopsy, and included mutations and gene copy number alteration analyses using high-throughput technologies, as well as the determination of oestrogen, progesterone, and androgen receptors by immunohistochemistry (IHC).Results:Biopsy was safely performed in 95 of the first 100 included patients. Median time between the biopsy and the therapeutic decision taken during a weekly molecular biology board was 26 days. Mutations, gene copy number alterations, and IHC analyses were successful in 63 (66%), 65 (68%), and 87 (92%) patients, respectively. A druggable molecular abnormality was present in 38 patients (40%).Conclusions:The establishment of a comprehensive tumour molecular profile was safe, feasible, and compatible with clinical practice in refractory cancer patients.

Pyrophosphorolysis-activated polymerization detects circulating tumor DNA in metastatic uveal melanoma.

Purpose: To develop a molecular tool to detect circulating tumor–derived DNA (ctDNA) in the plasma from patients with uveal melanoma as a marker of tumor burden and monitor treatment efficacy. Experimental Design: A real-time PCR was developed on the basis of bidirectional pyrophosphorolysis-activated polymerization (bi-PAP) for the quantification of ctDNA using 3′blocked primer pairs specific for the 3 recurrent mutually exclusive mutations of Gα subunits GNAQ and GNA11. Results: Sensitivity and specificity of bi-PAP were assessed on serial dilutions of tumor DNA in normal DNA for the 3 recurrent mutations. Each assay could detect a single mutated molecule per reaction, whereas 104 copies of normal DNA were not detected. The ctDNA was readily detected in plasma of mice bearing uveal melanoma xenografts in amounts proportional to circulating human DNA. Finally, plasma was almost always found positive (20 of 21 tested patients) in a prospective analysis of patients with metastatic uveal melanoma. Conclusions: Bi-PAP assays detect and quantify ctDNA in patients with metastatic uveal melanoma. A prospective study is ongoing to assess the clinical usefulness of ctDNA level in uveal melanoma. Clin Cancer Res; 18(14); 3934–41. ©2012 AACR.

Intraabdominal desmoplastic small round cell tumor: report of a case with fine needle aspiration, cytologic diagnosis and molecular confirmation.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a recently described neoplasm. This entity is well defined, with distinct clinical, pathologic and immunohistochemical features. Molecular studies have shown a specific reciprocal translocation t(11;22)(p13;q12). To our knowledge, no report of DSRCT with molecular confirmation on cytologic material has been reported before. CASE: Fine needle aspiration (FNA) was performed on an intraabdominal mass in a 37-year-old man. A May-Grunwald-Giemsa-stained preparation showed clusters of small round tumor cells associated with desmoplastic stromal cells, highly suggestive of DSRCT. FNA of a supraclavicular node showed cytologic features similar to those of the primary abdominal mass, including a prominent desmoplastic reaction of the stroma. Immunocytochemical studies showed myogenic and epithelial differentiation. Molecular analysis was performed on FNA, revealing the EWS/ WT1 chimeric transcript and thus confirming the cytologic diagnosis. CONCLUSION: Cytomorphologically, a definitive diagnosis of DSRCT may be difficult, as this tumor bears considerable resemblance to other small round cell tumors. The diagnosis can be confirmed by ancillary techniques, such as immunocytochemistry, and particularly by molecular analysis, which may also be performed on cytologic material.

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

Background Pembrolizumab and nivolumab are immune checkpoint inhibitors targeting PD-1 that have recently been approved in pretreated recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK). Patients and methods We retrospectively compared TGK on immunotherapy and TGK on last treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR ≥ 2. Results From September 2012 to September 2015, 34 patients were identified. Patterns of recurrence included exclusive loco-regional recurrence in 14 patients, exclusive distant metastases in 11 patients, and both in 9 patients. No pseudo-progression was observed. Hyperprogression was observed in 10 patients (29%), including 9 patients with at least a locoregional recurrence, and only 1 patient with exclusively distant metastases. Hyperprogression significantly correlated with a regional recurrence (TGKR ≥ 2: 90% versus TGKR < 2: 37%, P = 0.008), but not with local or distant recurrence. Hyperprogression was associated with a shorter progression-free survival (PFS) according to RECIST (P = 0.003) and irRECIST (P = 0.02), but not with overall survival (P = 0.77). Conclusions Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.

Preoperative staging of liver metastases from uveal melanoma by magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET)

BACKGROUND Microscopically complete (R0) resection of metastases from uveal melanoma prolongs median overall survival compared to incomplete surgery. The aim of this study was to compare the sensitivity of dynamic-enhanced magnetic resonance imaging (MRI) with fluorodeoxyglucose-positron emission tomography (FDG-PET) in the preoperative diagnosis of liver metastases from uveal melanoma. PATIENTS AND METHODS Fifteen consecutive patients (mean age: 56 years) underwent FDG-PET and liver MRI. Extrahepatic metastatic disease was excluded by whole body computed tomography and bone scintigraphy. MRI and FDG-PET were performed with a mean of 19 days (range: 1-30) before surgery. Imaging findings were compared with surgical (including intraoperative ultrasonography) and histological findings on a lesion by lesion analysis. RESULTS R0 resection was performed in 12 patients. A total of 28 lesions were resected with 27 histologically proven metastases. Nine lesions were smaller than 5mm, 7 measured 5-10mm and 11 were larger than 10mm. Sensitivity and positive predictive value were 67% and 95% for MRI compared to 41% and 100% for FDG-PET. The difference between the two modalities was statistically significant (p=0.01; McNemar test). In remaining 3 patients, diffuse miliary disease (>10 capsular lesions) was discovered intraoperatively, and was suspected on preoperative MRI in 2 cases. Only one extrahepatic lesion identified by FDG-PET was falsely positive. CONCLUSIONS In this preliminary study, MRI was superior to FDG-PET for staging of liver metastases from uveal melanoma. Although miliary disease was suggested by MRI in some cases, preoperative confirmation remains imperfect.