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Background WNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose-­escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions. Patients and Methods Patients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose–limiting toxicities (DLTs) were observed. Primary endpoints were incidence of DLTs and exposure to WNT974 and encorafenib. Secondary endpoints were anti-tumor activity and safety. Results Twenty patients were enrolled (COMBO10, n = 4; COMBO7.5, n = 6; COMBO5, n = 10). DLTs were observed in 4 patients, including grade 3 hypercalcemia (COMBO10, n = 1; COMBO7.5, n = 1), grade 2 dysgeusia (COMBO10, n = 1), and lipase increased (COMBO10, n = 1). A high incidence of bone toxicities (n = 9) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Serious adverse events were reported in 15 patients, most frequently bone fracture, hypercalcemia, and pleural effusion. The overall response rate was 10% and disease control rate 85%; most patients achieved stable disease as their best response. Conclusion Concerns surrounding the safety and lack of preliminary evidence of improved anti-tumor activity of WNT974 + encorafenib + cetuximab, compared with previous encorafenib + cetuximab data, ultimately led to study discontinuation. Phase II was not initiated. Trial registration ClinicalTrials.gov, NCT02278133

BackgroundIn the midst of the COVID-19 pandemic, patients with cancer are regarded as a highly vulnerable population. Overall, those requiring hospital admission for treatment administration are potentially exposed to a higher risk of infection and worse outcome given the multiple in-hospital exposures and the treatment immunosuppressive effects.MethodsCOVINT is an observational study assessing COVID-19 incidence among patients receiving anticancer treatment in the outpatient clinic of the Istituto Nazionale dei Tumori di Milano. All consecutive patients with non-haematological malignancies treated with intravenous or subcutaneous/intramuscular anticancer therapy in the outpatient clinic were enrolled. The primary endpoint is the rate of occurrence of COVID-19. Secondary endpoints included the rate of COVID-19-related deaths and treatment interruptions. The association between clinical and biological characteristics and COVID-19 occurrence is also evaluated. COVID-19 diagnosis is defined as (1) certain if confirmed by reverse transcriptase PCR assay of nasopharyngeal swabs (NPS); (2) suspected in case of new symptoms or CT scan evidence of interstitial pneumonia with negative/not performed NPS; (3) negative in case of neither symptoms nor radiological evidence.ResultsIn the first 2 months (16 February–10 April 2020) of observation, 1081 patients were included. Of these, 11 (1%) were confirmed and 73 (6.7%) suspected for COVID-19. No significant differences in terms of cancer and treatment type emerged between the three subgroups. Prophylactic use of myeloid growth factors was adopted in 5.3%, 2.7% and 0% of COVID-19-free, COVID-19-suspected and COVID-19-confirmed patients (p=0.003). Overall, 96 (8.9%) patients delayed treatment as a precaution for the pandemic. Among the 11 confirmed cases, 6 (55%) died of COVID-19 complications, and anticancer treatment was restarted in only one.ConclusionsDuring the pandemic peak, accurate protective measures successfully resulted in low rates of COVID-19 diagnosis, although with high lethality. Prospective patients’ surveillance will continue with NPS and serology testing to provide a more comprehensive epidemiological picture, a biological insight on the impact of cytotoxic treatments on the immune response, and to protect patients and healthcare workers.

Background Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. Material and methods TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. Results From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was Conclusions The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov , registration number: NCT0064660.

Background: In the midst of COVID-19 pandemic, cancer patients (pts) are regarded as a highly vulnerable population Pts requiring hospital admission for treatment (Tx) administration are potentially exposed to a higher risk of infection and worse outcome given the multiple in-hospital exposures and the Tx immunosuppressive effects Methods: COVINT is an observational study assessing COVID-19 incidence among pts receiving anticancer Tx in the outpatient clinic of the Istituto Nazionale dei Tumori di Milano All consecutive pts with non-hematologic malignancies treated with intravenous or subcutaneous/intramuscular Tx in the outpatient clinic were enrolled Pts were admitted to the clinic wearing surgical masks and only if asymptomatic and afebrile The primary endpoint is the rate of occurrence of COVID-19 Secondary endpoints include the rate of COVID-19 related deaths and Tx interruptions The association between clinical and biological characteristics and COVID-19 occurrence is also evaluated using nonparametric tests COVID-19 diagnosis is defined as: a) certain if confirmed by RT-PCR assay of nasopharyngeal swabs (NFS);b) suspected in case of new symptoms and/or CT scan evidence of interstitial pneumonia with negative/not performed NFS;c) negative in case of neither symptoms nor radiological evidence Results: In the first two months (16th February-10th April 2020) of observation, 1083 pts were included Of these, 11 (1%) were confirmed and 73 (6 7%) suspected for COVID-19 No significant differences in terms of cancer and Tx type emerged between the three subgroups Prophylactic use of myeloid growth factors was adopted in 5 3%, 2 7% and 0% of COVID-19-free, -suspected and -confirmed pts (p=0 003) Overall, 96 (8 9%) pts delayed Tx as a precaution for the pandemic Among the 11 confirmed cases, 6 (55%) died of COVID-19 complications, and anticancer Tx was restarted in only one Conclusions: During the pandemic peak, accurate protective measures successfully resulted in low rates of COVID-19 diagnosis, though with high lethality Within the COVINT study, prospective pts surveillance will continue with NFS swabs and IgG/IgM serology performed before each Tx cycle until pandemic resolution Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: F G M De Braud: Advisory/Consultancy: Tiziana Life Sciences;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS;Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene;Advisory/Consultancy, Research grant/Funding (institution): Novartis;Advisory/Consultancy: Servier;Advisory/Consultancy: Pharm Research Associated;Advisory/Consultancy: Daiichi Sankyo;Advisory/Consultancy, Speaker Bureau/Expert testimony: Ignyta;Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer;Advisory/Consultancy: Octimet Oncology;Advisory/Consultancy, Research grant/Funding (institution): Incyte;Advisory/Consultancy: Pierre Fabre;Advisory/Consultancy: Eli Lilly;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche;Advisory/Consultancy: Astra Zeneca;Advisory/Consultancy: Gentili;Advisory/Consultancy, Speaker Bureau/Expert testimony: Dephaforum;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): MSD;Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer;Advisory/Consultancy: Fondazione Menarini;Research grant/Funding (self): NMS;Research grant/Funding (institution): Merck KGAA;Research grant/Funding (institution): Kymab;Research grant/Funding (institution): Tesaro;Speaker Bureau/Expert testimony: Biotechespert Ltd;Speaker Bureau/Expert testimony: Prime Oncology All other authors have declared no conflicts of interest

Purpose Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. Methods This was a phase I dose-escalation (3 + 3 design [50–740 mg/m 2 ]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. Results In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m 2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m 2 , five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. Conclusion The MTD of once-weekly SAR125844 was 570 mg/m 2 ; SAR125844 was well tolerated, with significant antitumour activity in patients with MET -amplified NSCLC. Clinical trial registration number: NCT01391533

Previous works linked low sodium concentration with mortality risk in cancer. We aimed at weighing the prognostic impact of hyponatremia in all consecutive patients with metastatic solid tumors admitted in a two-years period at our medical oncology department. Patients were included in two cohorts based on serum sodium concentration on admission. A total of 1025 patients were included, of whom 279 (27.2%) were found to be hyponatremic. The highest prevalence of hyponatremia was observed in biliary tract (51%), prostate (45%) and small-cell lung cancer (38.9%). With a median follow-up of 26.9 months, median OS was 2 months and 13.2 months for the hyponatremia versus control cohort, respectively (HR, 2.65; P P

Background: The risk of venous thromboembolic events (VTE) during adjuvant chemotherapy for colorectal cancer (CRC) is unknown. We aim to evaluate if the Khorana score (KS) can predict this risk, and if it represents a prognostic factor for overall survival (OS) through a post hoc analysis of the phase III TOSCA trial of different durations (3- versus 6-months) of adjuvant chemotherapy. Methods: A logistic regression model was used to test the associations between the risk of VTE and the KS. The results are expressed as odds ratios (OR) with 95% confidence intervals (95% CI). To assess the effect of the KS on OS, multivariable analyses using Cox regression models were performed. The results are expressed as hazard ratios (HR) with 95% CI. Results: Among 1380 CRC patients with available data, the VTE risk ( n = 72 events: 5.2%) was similar in the two duration arms (5.5% versus 4.9%), with 0.2% of patients belonging to the high-risk KS group. Rates of VTE were similar in the low- and intermediate-risk groups (4.8% versus 6.4%). KS did not represent an independent predictive factor for VTE occurrence. Chemotherapy duration was not associated with VTE risk. In addition, KS was not prognostic for OS in multivariate analysis (HR: 0.92, 95% CI, 0.63–1.36; p = 0.6835). Conclusions: The use of the KS did not predict VTEs in a low–moderate thromboembolic risk population as CRC. These data did not support the use of KS to predict VTE during adjuvant chemotherapy, and suggest that other risk assessment models should be researched.

Background Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. Materials and Methods This is a substudy conducted in patients with high-risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse-free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. Results Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow-up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48–4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69–3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. Conclusions Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine-oxaliplatin chemotherapy. Larger studies and longer follow-up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. Implications for Practice The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low-dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.

The need to identify biomarkers for bevacizumab-based treatment in advanced colorectal cancer is imperative. The aim of this study was to investigate the prognostic role of circulating VEGF, PDGF, SDF-1, osteopontin and CEA in patients randomly assigned to three bevacizumab-based regimens. Plasma samples from 50 patients treated at a single Institution were analysed using the multiplex assay BioPlex™ 2200 (Bio-Rad Laboratories, Inc, Berkeley, CA, USA) at baseline, before first three cycles and subsequently every three cycles until disease progression. Prognostic analyses of baseline values were performed using multivariable Cox models, including disease extension >10 cm or ≤10 cm (measured as the sum of the diameters for all target lesions) as adjustment factor. The association between progression-free and overall survival and biomarkers modulation during treatment was studied using multivariable Cox models, which included summary statistics synthesizing during-treatment modulation together with disease extension. The biomarkers significantly associated with disease extension were baseline CEA (p = 0.012) and SDF-1 (p = 0.030). High values of VEGF and SDF-1 tended to be associated with worse prognosis, especially in terms of overall survival. The negative prognostic trend was more marked for baseline CEA as compared to other biomarkers; increasing values during treatment was significantly related to worse prognosis independently of disease extension (p = 0.007 and 0.016 for progression-free and overall survival, respectively). VEGF is related to bevacizumab pharmacodynamics and is associated to other angiogenic cytokines; some of the proposed biomarkers such as SDF-1 and CEA should be further validated for prognosis assessment and monitoring of bevacizumab-based treatment of advanced colorectal cancer.

Aim: Data from two randomized trials were pooled to further characterize the effectiveness of palonosetron combined with dexamethasone in the setting of highly emetogenic chemotherapy. Patients & methods: The analysis included 1411 patients who were randomized to receive palonosetron or ondansetron/granisetron intravenously on day 1 plus either 1-day or 3-day dexamethasone dosing. The primary end point was complete response (no vomiting and no rescue antiemetics over days 1–5) in cycle one. Data across the studies were analyzed by the Mantel–Haenszel method. Results: The vast majority of patients received either cisplatin (62%) or anthracycline plus cyclophosphamide (34%). The palonosetron regimen provided a 12 percentage-point improvement in the rate of overall complete response compared with the control regimen (49.2 vs 37.3%; odds ratio: 1.65; 95% CI: 1.33–2.04; p < 0.0001). The frequency of no delayed nausea at all daily periods was consistently higher in the palonosetron group. Conclusion: The current analysis confirmed that palonosetron plus dexamethasone improved control of highly emetogenic chemotherapy-induced nausea and vomiting throughout 5 days postchemotherapy to a significantly greater extent than the combination including older 5-HT3 antagonists.

A phase I/II study was performed to determine the safety and activity of a capecitabine plus oxaliplatin and irinotecan (COI) regimen using capecitabine concurrently with oxaliplatin and irinotecan in previously untreated patients with metastatic colorectal cancer.Patients received irinotecan on day 1, oxaliplatin (85 mg/m(2)) on day 2 and capecitabine (1000 mg/m(2) orally twice daily) on days 2-6 of a biweekly schedule. Three dose levels ranging from 150 to 180 mg/m(2) were explored for irinotecan in sequential cohorts of three to six patients. Once the recommended dose was determined, a total of 28 eligible patients were planned at this dose level.Thirty-eight patients received a median of six cycles. The recommended phase II dose of irinotecan was 180 mg/m(2). Toxicity was manageable: the most common severe toxicities were diarrhoea (24%) and nausea (16%). Of 27 assessable patients treated at the recommended dose, 17 achieved a partial response (overall response rate (ORR) 63%; 95% confidece interval (CI), 44 to 78%), with eight patients undergoing liver metastasectomy. Estimated progression-free survival and overall median survival were 8.5 and 23.5 months, respectively.Biweekly COI is feasible and active. Tolerability and ease of administration make the regimen well suited for downsizing hepatic colorectal metastases before curative surgery.

In a phase II study, we showed that temozolomide (TMZ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer (CRC) and MGMT methylation. A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion, even in resistant tumors. Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75 mg/m2 for 21 consecutive days every 4 weeks, for up to six cycles or until the occurrence of progressive disease/unacceptable toxicity. The primary endpoint was treatment activity in terms of objective response rate (ORR). MGMT protein expression was tested by immunohistochemistry (IHC) on two pooled cohorts: patients from the previous study of standard-dose TMZ and those from the current investigation. From November 2013 to December 2014, 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori. We observed only three episodes of grade 3 asthenia and no significant myelotoxicity. The ORR was 16 % (all partial responses occurring in RAS-BRAF-mutated tumors). Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.7 months, respectively. Patients with MGMT-low expression by IHC had a significantly higher ORR (p

Background A dose-finding phase I/II trial that evaluated the maximum tolerated doses of a combination of three drugs with irinotecan, oxaliplatin and capecitabine (COI regimen) has been conducted in patients with metastatic colorectal cancer (mCRC). In this study the safety and activity of the combination of COI regimen plus bevacizumab (COI-B) were assessed. Methods Patients judged to be unresectable for metastatic disease, were enrolled in a phase II, open-label study and treated with the combination of bevacizumab (5 mg/kg on day 1) and COI regimen (irinotecan 180 mg/mq on day 1, oxaliplatin 85 mg/mq on day 2, capecitabine 2000 mg d2–6; q14) as first-line treatment. Induction treatment was administered for a maximum of 8 cycles, followed by maintenance treatment with bevacizumab (7.5 mg/kg on d1, q21) until progression. Results Fifty-one patients were enrolled in six Italian centres. The primary end-point of overall response rate was met, reaching the value of 62% in the per-protocol population and 57% in the intent-to-treat population, patients with stable disease were also taken into account, the clinical benefit rate was 94%. In the intention-to-treat population, median progression-free and overall survivals were 10.3 and 22 months, respectively. Toxicity was different from 5-fluorouracil-based triplet regimens, with 31% of severe diarrhoea, but a low incidence of grade 3/4 neutropenia (6%) and mucositis (4%). Conclusions Our results show the feasibility and promising activity of the combination of capecitabine, oxaliplatin, irinotecan and bevacizumab.

Objectives The aim of this study was to evaluate the feasibility and tolerability of capecitabine administration according to a specific time schedule, combined with adjuvant radiation therapy, in intermediate-risk to high-risk rectal cancer patients treated with an upfront surgery. The primary endpoint was the rate of grade 3 to 4 diarrhea during chemoradiation (CRT). Materials and methods Stage II and III rectal cancer patients received, after total mesorectal excision, 2 cycles of XELOX regimen (oxaliplatin 130 mg/m(2) on day 1; capecitabine 1000 mg/m(2) bid on day 1 to 14, q21), followed by capecitabine (800 mg/m(2) bid daily; 20% dose at 12:00 AM and 80% dose at 12:00 PM) administered continuously during pelvic radiation (total 50.4 Gy in 28 fractions, 1.8 Gy daily dose between 2:00 and 4:00 PM). Four additional cycles of XELOX were administered after chemoradiotherapy. Results Fifty-one radically resected rectal cancer patients were enrolled. All, but one, cases were evaluated for safety of CRT. We reported a grade 3 and 4 diarrhea rate of 14% (7 of 50 patients), whereas no grade 3 and 4 leukopenia was observed. Grade 1 and 2 proctitis was observed in 26 (52%) cases, whereas grade 1 and 2 cystitis in 5 (10%) patients. Only 2 cases of grade 3 proctitis and cystitis were reported, respectively. The CRT phase was feasible and was completed by 43 (84%) patients. Three patients developed actinic enteritis 60 days after the end of the radiotherapy program. Conclusions Capecitabine timetable administration combined with adjuvant radiation therapy of rectal cancer is well tolerated and feasible. Further investigation of this chronomodulated schedule in terms of efficacy is warranted in neoadjuvant setting.

There is conflicting evidence on the predictive role of KRAS status when cetuximab is added to oxaliplatin-based regimens. This study investigated the impact of KRAS, NRAS, BRAF, PI3KCA and TP53 status on outcome of elderly metastatic colorectal cancer patients enrolled in TEGAFOX-E (cetuximab, oxaliplatin and oral uracil/ftorafur—UFT) phase II study. Twenty-eight patients were enrolled and all were evaluable for safety and activity. Twenty-three specimens were analysed for KRAS, BRAF, NRAS, PI3KCA and TP53 mutational status by means of polymerase chain reaction and correlated with objective response, progression-free survival and overall survival. An evident increase of response rate was noted in KRAS/NRAS wild-type cases (70 versus 33 %, P = 0.198). KRAS/NRAS wild-type status showed an independent association with a longer progression-free survival (44 versus 9 weeks, P = 0.009). Considering the combined assessment of BRAF, KRAS/NRAS and TP53, a trend towards an increase of response rate was noted in patients without mutations (83 versus 33 %, P = 0.063). Moreover, patients with all wild-type genes had significantly longer progression-free survival than patients with any mutation (48 versus 10 weeks, P = 0.007). As a single biomarker, only KRAS/NRAS proteins maintained an independent value for outcome prediction. Patients with KRAS/NRAS, BRAF and TP53 wild-type tumours could derive the maximal benefits from treatment with cetuximab, oxaliplatin and UFT.

Background: Tyrosine kinase receptors are important regulators of cellular signal transduction pathways that play a crucial role in development of cancer. Among them, Anaplastic Lymphoma Kinase (ALK) and C-Ros Oncogene-1 (ROS-1) are activated by rearrangement in several tumors. Tailored therapies have been developed according to the status of ALK and ROS-1, successfully used in NSCLC and potentially useful in other solid tumors harboring ALK and ROS-1 aberrations. Material and methods: ALK and ROS-1 status was evaluated in 666 and 441 patients with solid tumors, respectively, since 2014 at the Pathology Department. ALK and ROS-1 rearrangement and gene copy number variation (CNV) were assayed by fluorescence in situ hybridization (FISH). Gene copy number gain was defined by 3 to 5 fusion signals on average in ≥10% of cells, with amplification being highlighted by the clusters or 10 to 15 fusion signals in 10% or more tumor cells. Results: ALK status was assessed in 650/666 (97%) cases, while ROS-1 status was evaluable in 426/441 (96%). We identified 15/650 (2.3%) cases with ALK rearrangment, including 13 lung adenocarcinomas (4.1%), 1 colon cancer (0.5%) and 1 myoepithelioma (0.5%). CNV for ALK was documented in 53% lung adenocarcinoma, 50% pancreatic, 41% biliary and 37% colon carcinoma patients. We found 7/426 (1.6%) tumors with ROS-1 rearrangement, corresponding to 5 lung (2.7%) and 2 colon (1.3%) adenocarcinomas. CNV for ROS-1 was more frequent in melanoma (77%), neuroendocrine tumors (39%) and NSCLC (32%, 3/4 cases of ROS-1 amplification were squamous carcinoma). Eight out of the 22 rearranged cases (5 ALK and 3 ROS-1) were tested for both genes: these aberrations were mutually exclusive. Three out of 5 (60%) ALK rearranged tumors showed ROS-1 deletion. No ALK and ROS-1 alterations were documented in 30 pancreatic, 25 H&N, 22 biliary tract, 13 renal, and 13 breast carcinomas, as well as in 13 melanomas and 36 other solid tumors. Conclusions: ALK and ROS-1 rearrangement was found in 4.1% and 2.7% of NSCLC, respectively, in keeping with literature data. In other solid tumors, the percentage of rearrangements is exceedingly low, but melanoma, neuroendocrine tumors, pancreatic and colon cancer may show significant CNV. We speculate that such aberrations of ALK and ROS-1 could act as potential therapy targets, but additional investigation by immunohistochemistry and next generation sequencing is clinically warranted. Citation Format: Maria Silvia Cona, matteo Duca, Adele Testi, Sara Cresta, Katia Fiorella Dotti, Alice Indini, Diego Signorelli, Giuseppe Pelosi, Filippo Guglielmo de Braud, Silvia Damian. ALK and ROS-1 status: A retrospective analysis in solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A08.

A 48-year-old man was referred to our hospital with the diagnosis of colon cancer with multiple hepatic metastases. After right hemicolectomy, the rapid progression of liver disease was treated with metronomic capecitabine and bevacizumab according to a study protocol. A gradual regression of metastatic lesions was observed during a 9-month treatment period. After conversion of liver disease to resectability, the histological examination disclosed the complete necrosis of all lesions, with the exception of small neoplastic foci inside a single nodule. The comparison of this type of histological findings with the classic sclero-hyaline pathological response, as well as its importance as indicator of response to antiangiogenic treatment, is discussed.

This study evaluated the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine in pre-treated metastatic colorectal cancer patients.Five dose level combinations with irinotecan (from 180 to 240 mg/m(2), day 1, q21), capecitabine (1,500-2,000 mg/m(2) per day, days 2-15, q21) and erlotinib (50-150 mg per day, continuously) were planned. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity.Twenty-one patients were treated. In the first cohort, no DLT was reported, in the second: one DLT (G4 neutropenic fever associated with G3 cutaneous rash and mucositis); in the third dose level: two DLT (G3 diarrhea and G4 neutropenic fever). To confirm these results, other six patients were additionally included and no DLT was observed.The results documented that erlotinib at the dose of 100 mg per day, irinotecan 180 mg/m(2) and capecitabine 1,500 mg/m(2) per day for 14 days has an acceptable safety profile and appears suitable for further phase II studies.

Background: We showed that standard dose TMZ (150 mg/mq/day day1-5q28) is tolerable and active in 32 heavily pre-treated patients with advanced CRC and MGMT promoter methylation (Pietrantonio et al., Ann Oncol 2014). In a subsequent study, we included 32 pts treated with dose-dense TMZ (75 mg/mq/day day 1-21q28, for up to 6 cycles or until progression/unacceptable toxicity). Additional predictive markers are needed for improved selection of patients for TMZ therapy in metastatic CRC. Retained MGMT expression by IHC was proposed as marker for negative selection of pts with brain tumors. We conducted a retrospective analysis to assess MGMT expression in our 2 studies and to correlate this with the outcomes. Methods: All 64 patients included in the 2 studies were defined as MGMT methylation-positive according to methylation-specific PCR. A total of 40 patients had tissue available for IHC. Expression of nuclear MGMT protein was defined scored semiquantitatively according to extension and intensity. Using ROC analysis, IHC score Results: Herein, we report for the first time the results of the dose-dense TMZ study. We obtained 4 confirmed partial responses and 2 stable disease, accounting for a response rate of 12% and a clinical benefit of 18%. Median PFS was 1.8 months. OS data are not mature. Thus, the results are comparable to those obtained in the previous study. MGMT-low expression was found in 15 (38%) samples and MGMT-high in 25 (62%). RAS-BRAF mutations were found in 28 (70%) pts and were not correlated with MGMT expression (p = 1). Response rate was significantly higher in patients with MGMT-low (53%) vs. those with MGMT-high (p Conclusions: In this translational study on MGMT methylated CRC, absence of MGMT expression was significantly correlated with tumor response and benefit from TMZ treatment. Citation Format: Filippo De Braud, Filippo Pietrantonio, Maria Di Bartolomeo, Katia Fiorella Dotti, Claudia Maggi, Roberto Iacovelli, Marta Caporale, Rosa Berenato, Federica Perrone, Elena Tamborini, Alessio Pellegrinelli, Stefano Federici, Fabrizio Festinese, Giuseppe Pelosi, Ilaria Bossi, Paola Valentina Consonni, Susanna Maggi, Massimo Milione. MGMT immunohistochemistry (IHC) improves patients’ selection for temozolomide (TMZ) treatment in advanced chemorefractory MGMT-methylated colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-119. doi:10.1158/1538-7445.AM2015-LB-119

202 Background: Codon 12 KRAS and BRAF mutations may have a role in the mucinous differentiation pathway in colorectal cancer (Bazan V et al, Ann Oncol 2002; Tran et al, Cancer 2011). Elucidating the molecular mechanisms driving this disease is a priority for PMP, with the goal of identifying new markers and therapeutic targets needed to improve disease management. Due to the fact that neoplastic cells may be deceptively bland and sparse histologically within an abundant mucinous background, the adoption of high-sensitivity gene sequencing techniques may be extremely helpful. Methods: Mucinous tumors from 10 PMP cases of appendiceal origin treated in a multidisciplinary team at the National Cancer Institute of Milan were histologically classified according to Bradley classification. Following microdissection and DNA extraction, mutational analysis of KRAS exon 2-4 and BRAF exon 15 were performed by means of PCR, while KRAS exon 2 status was further confirmed through a specific mutant enriched PCR, shown to be a more sensitive approach in colorectal cancer (Molinari et al, Clin Cancer Res 2011). Results: Histological classification was low-grade in 6 and high-grade in 4 tumors. Codon 12 KRAS mutations were detected in 5/10 cases (50%). In the remaining 5 cases: sequencing of exon 4 lead to identification of a first-described A146V mutation in 1 case; with mutant enriched technique, we identified 3 additional codon 12 mutated cases. Due to use of high sensibility techniques and gene sequencing outside hotspot regions, we were able to identify KRAS mutations in 9/10 (90%) specimens. No BRAF exon 15 mutation was detected. Conclusions: The prognostic role of KRAS mutation in PMP patients is under investigation on a larger data-set of National Cancer Institute of Milan and will be presented at the Meeting. However, these preliminary data suggest a major role of KRAS in the carcinogenesis of mucinous tumors of appendiceal origin with PMP.

e21118 Background: A favourable outcome is associated with pCR in LARC treated with NACR; pCR prediction through functional imaging may help the prospective evaluation of management strategies alternative to standard surgery. The aim of this prospective study was to identify whether FDG-PET activity and early/late response predicted independently pCR. Methods: Patients with histologically diagnosed cT3-4 and/or N+ primary rectal cancer were treated homogeneously with NACR (simultaneous boost technique radiotherapy 54 Gy on GTV/24 fractions plus capecitabine 1650 mg/mq/day) and total mesorectal excision 7-8 weeks later. FDG-PET uptake, expressed as maximum standardized uptake value, was obtained at baseline (SUV-1), at interim (2 weeks after treatment start: SUV-2) and 6 weeks after NARC completion (SUV-3) and was calculated as percentage difference (Δ-SUV). The role of SUV-1, SUV-2, SUV-3, Δ-SUV(1-2) and Δ-SUV(1-3) for pCR prediction was assessed using logistic regression analysis; ROC analysis was performed to identify the optimal thresholds. Results: The study enrolled 30 pts (median age 59 yrs; 12M:18F) treated from January 2009 to November 2011 at Istituto Nazionale Tumori of Milan. All underwent FDG-PET at baseline and post-NACR and 80% consented to an interim assessment; one patient was excluded due to surgery refusal. pCR rate was 28%. Among all parameters, only post-NACR SUV (mean 4 +/- 1.7 for pCR vs 8.7 +/-5.8 for non-pCR; P=0.001 by Mann-Whitney test) showed significant association with pCR at univariate analysis (P=0.03). At multivariate analysis including baseline SUV, post-NACR SUV, Δ-SUV, age (≤ or >65 yrs), sex (F or M) and pre-treatment stage (N- or N+/cT3 or cT4), only female sex and post-NACR SUV predicted independently pCR (both P=0.01). With ROC analysis, a post-NACR SUV threshold

13075 Background: Erlotinib is an oral selective and reversible small molecule inhibitor with specificy for the EGFR/HER1. This study evaluated the maximum tolerated dose and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine. Secondary objectives included the safety profile and the response rate of the combination. Methods: Twenty-two pts (median age 57 yrs, range: 39–69; M/F:12/10) with mCRC refractory to first-line therapy (oxaliplatin-combinations) were accrued. Five dose level combinations with irinotecan (from 180 to 240 mg/m2, day 1, q21), capecitabine (1500 to 2400 mg/m2/d, days 2–15 q21) and erlotinib (50 to 150 mg/d., continuously until progression) were planned. Cycles were repeated every 3 weeks, maximum of 6–8 cycles. Tumor assessments (RECIST criteria) performed every 3 cycles. Maximum tolerated dose was defined as the highest dose where the toxicity rate does not exceed the 30% target level. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity. Results: Three pts entered the first dose group (no DLT), six the second (1 DLT; G4 neutropenic fever), six the third dose group (2 DLT; G3 diarrhea, G4 neutropenic fever), and one (protocol deviation in the dose escalation scheme) the fourth dose group (1 DLT; G3 diarrhea and vomiting). Cutaneous rash and mucositis G3 (no DLT), were documented in one pt (dose group 2). To confirm these results, six pts were additionally accrued in dose groups 2 and 3 showing no DLT. Among twenty evaluable pts, two had an objective response, 15 showed disease stabilization and completed the 6-cycle treatment, 3 had disease progression. Conclusions: Erlotinib at a dose of 100 mg/d, combined with irinotecan 240 mg/m2 and capecitabine 1500 mg/m2/d, (as correspond to dose group 3) has an acceptable safety profile and appears suitable for further investigation. Editorial Assistance by the Scientific Service of the I.T.M.O. group. No significant financial relationships to disclose.