Elena Magni

First clinical experience of orally active epidermal growth factor receptor inhibitor combined with simplified FOLFOX6 as first‐line treatment for metastatic colorectal cancer

Gefitinib, an orally active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, combined with chemotherapy, has shown efficacy as second‐line treatment for advanced colorectal cancer (CRC). Gefitinib combined with FOLFOX6 (oxaliplatin plus folinic acid and 5‐fluorouracil) was tested as a first‐line therapy.

The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death

Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS–ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.

K-ras status in squamous cell anal carcinoma (SCC): it's time for target-oriented treatment?

PurposeSquamous cell anal carcinoma (SCC) is an uncommon disease comprising only 1–5% of all intestinal tumours. SCC is now considered the prototype for the successful application of conservative treatment as chemoradiation instead of aggressive surgery. The EGFR status and k-ras mutations in SCC of the anal canal has not been well investigated. The purpose of our evaluation was to give information about this issue.MethodsFrom June 1999 to December 2008, 32 patients affected by SCC were treated in our institution with chemotherapy containing fluoropyrimidine and platinum salt concomitant with pelvic radiotherapy. Immunohistochemistry for EGFR and k-ras mutation was retrospectively evaluated.ResultsTwenty-six specimens were considered evaluable for biological objectives: K-ras mutation was performed in all cases, while EGFR in 12. In all cases of our series wild-type K-ras was observed.ConclusionsSuch information is, in our knowledge, the first reported in literature on this setting. This observation previously reported in other tumours has supported the effective use of EGFR-inhibitors in recurrent or metastatic disease. This observation could support the role of EGFR-inhibitors in the treatment of SCC.

Capecitabine Initially Concomitant to Radiotherapy Then Perioperatively Administered in Locally Advanced Rectal Cancer

PURPOSE To evaluate the impact of neoadjuvant capecitabine, concomitant to radiotherapy, followed by capecitabine monotherapy, in operable locally advanced rectal cancer (LARC) by measuring pathologic response and conservative surgery rate, toxicity profile, and disease-free survival (DFS). METHODS AND MATERIALS From October 2002 to July 2006, a total of 51 patients affected by LARC (T3-T4 or any node positive tumor), received capecitabine (825 mg/m(2), orally, twice daily continuously) concomitant to radiotherapy on the pelvis (50.4 Gy/ 28 fractions), followed by two cycles of capecitabine (1,250 mg/m(2), orally, twice daily, 14 days on 7 days off) up until 2 weeks before surgery. Tailored adjuvant systemic treatment was discussed according to pathologic stage. RESULTS Of 51 patients, (median age 61 years, range 38-82 years; 19 women and 32 men; ECOG performance status 0/1/2: 46/4/1), 50 were evaluable for response: 18% complete pathologic remission; 12% T-downstaging, and 30% N-downstaging. One patient died before surgery from mesenteric stroke. Grade 3 acute toxicities were 2% diarrhea, 8% dermatitis, 2% liver function test elevation, and 2% hand-foot syndrome. Sphincter preservation rates for tumors < or =6 cm from the anal verge were 62% and 80% for the whole population. Median follow up was 43.0 months (range 0.8-68.6 months). Five-years DFS was 85.4% (95% CI = 75.3-95.4%). CONCLUSIONS Based on our study results, we conclude that this regimen is well tolerated and active and compares favorably with existing capecitabine-based approaches.

Burned out phenomenon of the testis in retroperitoneal seminoma.

To the Editor A 42-year-old male patient presented to his local doctor with profuse night sweating and back pain. Multiple retroperitoneal lymph node metastases (from 2.1 to 3.5 cm masses) were found to the right of the aorta on the computed tomography (CT) scan. The masses displace the aorta, renal right arteria and cava vein with CT evidence of infiltration. A testicular ultrasound confirmed a 3.0 cm hypoechoic nodule within the left testicle; the right testicle was normal in size. Tumour marker b-human chorionic gonadotropin (b-HCG) was out of range (11 mUI/m) and a-fetoprotein (a-FP) was normal. Lactic dehydrogenase (LDH) was found out of

Effect of KRAS and BRAF Mutations on Survival of Metastatic Colorectal Cancer After Liver Resection: A Systematic Review and Meta-Analysis

Background: The purpose of the study was to evaluate whether the mutational status of Kirsten rat sarcoma viral oncogene homolog (KRAS) or b‐viral oncogene homolog B1 (BRAF) could be an independent prognostic factor in the subset of patients with colorectal cancer liver metastases (CRLM) who undergo complete liver resection. Materials and Methods: A systematic literature review was performed to identify articles reporting relapse‐free survival (RFS) and/or overall survival (OS) of patients who underwent complete liver resection for CRLM, stratified according to KRAS and BRAF mutational status. Hazard ratios (HRs) from multivariate analyses were pooled in the meta‐analysis. Results: Eleven studies, including 1833 patients, were eligible for the meta‐analysis. Nine of them reported OS stratified according to KRAS mutation. The pooled analysis revealed that KRAS mutation was negatively associated with OS (HR, 1.674; 95% confidence interval [CI], 1.341‐2.089; P < .001). Nine among 11 studies reported RFS stratified according to KRAS mutation and HRs in multivariate analysis were available in 7. In a pooled analysis, KRAS mutation was negatively associated with RFS (HR, 1.529; 95% CI, 1.287‐1.817; P < .001). In 3 studies HRs of the multivariate analysis regarding the OS according to BRAF mutational status were also available, showing a negative association with OS (HR, 3.055; 95% CI, 1.794‐5.204; P < .001). Conclusion: KRAS mutations are negatively associated with OS and RFS in patients who undergo complete liver resection for CRLM. A similar negative effect on OS was observed also for BRAF mutation, although fewer studies were included. These data support integration of KRAS and BRAF mutational status into a combined predictive score for prospective assessment of outcome after resection of CRLM in clinical studies. &NA; Treatment of metastatic colorectal cancer includes resection of liver metastases, however, no biomarkers drive selection of patients. We performed a meta‐analysis including 1833 patients treated with complete liver resection, showing that Kirsten rat sarcoma viral oncogene homolog and b‐viral oncogene homolog B1 mutations are negatively associated with survival. This supports integration of mutational status into a combined score to better identify candidates for resection of colorectal cancer liver metastases.

Treatments for colorectal liver metastases: A new focus on a familiar concept

A major challenge for the management of advanced-colorectal-cancer is the multidisciplinary approach required for the treatment of liver metastases. Reducing the burden of liver metastases with liver-directed therapy has an important impact on both survival and health-related quality of life. This paper debates the rationale and current liver-directed approaches for colorectal liver metastases based on the evidence of literature and new clinical trials. Surgery is the gold standard, when feasible, and its the main treatment goal for patients with potentially-resectable disease as a means of prolonging progression-free survival. Better tumor response rates with modern systemic therapy mean that more unresectable patients are now down-staged for radical resection following conversion therapy but for other patients, additional procedures are needed. In multiple unilobar disease, when the projected remnant liver is <30% of the total liver, portal embolization or selective-internal-radiation-therapy (SIRT) can induce hypertrophy of the healthy liver, leading to resectability. In multiple bilobar disease, in situ destruction of non-resectable lesions by minimally invasive techniques may be associated with liver resection to achieve potential curative intent. Other palliative liver-directed approaches, such as SIRT or intra-hepatic chemotherapy (HAI), which are associated with higher response rates, may also have role in down-staging patients for resection. Until recently, such technologies have not been validated in prospective controlled trials. However in the light of new Phase 3 data for SIRT as well as for HAI combined with modern therapies or radiofrequency ablation in the first- and second-line setting, the clinical value of these treatments needs to be re-appraised.

Primary pure gastric yolk sac tumor

We describe here a case of pure gastric yolk sac tumor (YST). A 62-year-old patient underwent gastrectomy with D2 dissection. The histological report confirmed the diagnosis of YST and that two of the 14 regional lymph nodes removed were metastatic. Three courses of PEB regimen chemotherapy were delivered subsequently. Three months later the patient experienced dysphagia from stenosis of the anastomosis and a computerized tomography scan showed tumor recurrence with peritoneal nodules; the patient died one year after surgery. The origin of gastric YST is unclear but involvement of migrating germ cells during embryonic development or multipotential neoplastic protoepithelial cells of the gastric mucosa have been suggested. Generally the prognosis of gastric YST is poor and the standard therapeutic approach beyond surgery is still uncertain.

Cisplatin, etoposide and continuous infusion bleomycin in patients with testicular germ cell tumors: Efficacy and toxicity data from a retrospective study

Abstract We retrospectively reviewed medical charts of 54 patients who underwent orchidectomy for germ cell tumors (GCT) and received a regimen, given every 3 weeks, consisting of cisplatin 100 mg/m2 day 4 intravenous (i.v.), bleomycin 15 Units (U) day 1 i.v. push; bleomycin 10 U days 1-3 24 h i.v. continuous infusion (c.i.) and etoposide 100 mg/m2 days 1-5/i.v. (PEB). 53 of 54 patients achieved a complete remission without adjunctive surgery. At a median follow-up of 48.2 months (95%CI 41.7 - 54.8 months) all patients but one are alive with no evidence of disease recurrence. Patients receiving PEB experienced no pulmonary toxicity, nephrotoxicity nor neurological adverse events. PEB with c.i. bleomycin is an active regimen with a low rate of acute and late toxicity. The main limitations of our study are related to the retrospective analysis, the limited number of patients and the restricted follow-up time. A prolonged follow- up is necessary to evaluate long term toxicity and outcome.

Abstract 627: Immunogenic cell death as novel immune response mechanism to EGFR-targeted therapy in CRC

Colorectal cancer (CRC) is the third most common cancer worldwide. The major improvement in the median overall survival of mCRC patients was mainly due to the introduction of new active chemotherapeutic and biomolecular targeting agents. Most chemotherapeutic agents and radiotherapy kill tumor cells through an apoptotic pathway, which is considered as a non-immunogenic. However, anthracyclines, oxaliplatin or ionizing irradiation are able to induce a potent immune response in vivo, when injected in immunocompetent mice. Dying cells are readily taken up by dendritic cells (DC) that then cross-present their associated antigens for effective T cell activation. Herein we propose that the treatment with an anti-EGFR antibody (Cetuximab) in combination with chemotherapy FOLFIRI (5-fluorouracile, leucovorin, irinotecan) induces a immunogenic cell death (ICD) modality, which contributes to its clinical efficacy in patients with mCRC expressing EGFR and the wild type (wt) form of the viral oncogene v-Ki ras2. Our results, obtained on CRC cell lines provide evidence, for the first time, that treatment with Cetuximab alone or in combination with a chemotherapeutic regimen (FOLFIRI) directs dying cells towards an ICD process characterized by phosphorylation of eIF2α and, most important, increased phagocytosis by DCs. However, not all cell lines wt for KRAS (expressing EGFR) displayed the same response. As expected, Cetuximab blocked the pathways leading to AKT and ERK phosphorylation. However, we also observed that Cetuximab, and to a lesser extent the F(ab)2 fragments of Cetuximab, was inducing some phosphorylation of the EGFR in KRAS wt responding cell line, which was lower than that induced by EGF . Hence Cetuximab is uncoupling the activation of the signaling pathway induced via EGFR from EGFR phosphorylation, suggesting an alternative activation of the receptor. This allowed us to postulate that Cetuximab-induced phagocytosis may be the effect of an alternative activation of the EGFR. Indeed, we could not detect any phagocytosis in cell lines where the phosphorylation of the receptor did not occur in response to Cetuximab. These results identify ICD as novel immune response mechanism to EGFR targeted therapy alone or in combination with chemotherapy and possibly genetic alterations of the EGFR-signalling pathway, could interfere with the induction of ICD. Citation Format: Giuseppe Penna, Chiara Pozzi, Elena Magni, Giuseppe Curigliano, Maria Giulia Zampino, Maria Rescigno. Immunogenic cell death as novel immune response mechanism to EGFR-targeted therapy in CRC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 627. doi:10.1158/1538-7445.AM2014-627