Manuel Gallen

Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer.

Antibodies against epidermal growth factor receptor (EGFR)—cetuximab and panitumumab—are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.

Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study.

PURPOSE The optimal therapeutic sequence of the adjuvant chemotherapy component of preoperative chemoradiotherapy (CRT) for patients with locally advanced rectal cancer is controversial. Induction chemotherapy before preoperative CRT may be associated with better efficacy and compliance. PATIENTS AND METHODS A total of 108 patients with locally advanced rectal cancer were randomly assigned to arm A-preoperative CRT with capecitabine, oxaliplatin, and concurrent radiation followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-induction CAPOX followed by CRT and surgery. The primary end point was pathologic complete response rate (pCR). Results On an intention-to-treat basis, the pCR for arms A and B were 13.5% (95% CI, 5.6% to 25.8%) and 14.3% (95% CI, 6.4% to 26.2%), respectively. There were no statistically significant differences in other end points, including downstaging, tumor regression, and R0 resection. Overall, chemotherapy treatment exposure was higher in arm B than in arm A for both oxaliplatin (P < .0001) and capecitabine (P < .0001). During CRT, grades 3 to 4 adverse events were similar in both arms but were significantly higher in arm A during postoperative adjuvant CT than with induction CT in arm B. There were three deaths in each arm during the treatment period. CONCLUSION Compared with postoperative adjuvant CAPOX, induction CAPOX before CRT had similar pCR and complete resection rates. It did achieve more favorable compliance and toxicity profiles. On the basis of these findings, a phase III study to definitively test the induction strategy is warranted.

Circulating Tumor Cell Count Is a Prognostic Factor in Metastatic Colorectal Cancer Patients Receiving First-Line Chemotherapy Plus Bevacizumab: A Spanish Cooperative Group for the Treatment of Digestive Tumors Study

BACKGROUND The Maintenance in Colorectal Cancer trial was a phase III study to assess maintenance therapy with single-agent bevacizumab versus bevacizumab plus chemotherapy in patients with metastatic colorectal cancer. An ancillary study was conducted to evaluate the circulating tumor cell (CTC) count as a prognostic and/or predictive marker for efficacy endpoints. PATIENTS AND METHODS One hundred eighty patients were included. Blood samples were obtained at baseline and after three cycles. CTC enumeration was carried out using the CellSearch® System (Veridex LLC, Raritan, NJ). Computed tomography scans were performed at cycle 3 and 6 and every 12 weeks thereafter for tumor response assessment. RESULTS The median progression-free survival (PFS) interval for patients with a CTC count ≥3 at baseline was 7.8 months, versus the 12.0 months achieved by patients with a CTC count <3 (p = .0002). The median overall survival (OS) time was 17.7 months for patients with a CTC count ≥3, compared with 25.1 months for patients with a lower count (p = .0059). After three cycles, the median PFS interval for patients with a low CTC count was 10.8 months, significantly longer than the 7.5 months for patients with a high CTC count (p = .005). The median OS time for patients with a CTC count <3 was significantly longer than for patients with a CTC count ≥3, 25.1 months versus 16.2 months, respectively (p = .0095). CONCLUSIONS The CTC count is a strong prognostic factor for PFS and OS outcomes in metastatic colorectal cancer patients.

Mitogen-activated protein kinase phosphatase-1 (MKP-1) impairs the response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab in metastatic colorectal cancer patients

Background:The validation of KRAS mutations as a negative marker of response to anti-epidermal growth factor receptor (EGFR) antibodies has meant a seminal advance towards treatment individualisation of colorectal cancer (CRC) patients. However, as a KRAS wild-type status does not guarantee a response to anti-EGFR antibodies, a current challenge is the identification of other biomarkers of response. On the basis of pre-clinical evidence, we hypothesised that mitogen-activated protein kinase phosphatase-1 (MKP-1), a phosphatase that inactivates MAPKs, could be a mediator of resistance to anti-EGFR antibodies.Methods:Tumour specimens from 48 metastatic CRC patients treated with cetuximab-based chemotherapy were evaluated for KRAS and BRAF mutational status and MKP-1 expression as assessed by immunohistochemistry.Results:As expected, clinical benefit was confined to wild-type KRAS and BRAF patients. Mitogen-activated protein kinase phosphatase-1 was overexpressed in 16 patients (33%) and was not associated with patient baseline clinicopathological characteristics and KRAS mutational status. All patients with BRAF mutations (n=3) had MKP-1 overexpression. Among KRAS wild-type patients, MKP-1 overexpressors had a 7% response rate (RR), whereas patients not overexpressing MKP-1 had a 44% RR (P=0.03). Moreover, median time to progression was significantly longer in MKP-1 non-overexpressing patients (32 vs 13 weeks, P=0.009).Conclusion:These results support the concept of MKP-1 as a promising negative marker of response to cetuximab-based treatment in CRC patients with wild-type KRAS.

Prognostic Value of the Combination of Circulating Tumor Cells Plus KRAS in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab

OBJECTIVE Circulating tumor cells (CTCs) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) status were identified as prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab in analyses of the MACRO (Maintenance Treatment in Advanced Colorectal Cancer) trial. In this post hoc analysis of the MACRO trial, the potential additive effect of these 2 factors on patient outcomes was explored. METHODS A total of 158 of the 480 patients involved in the MACRO trial were included in the biological marker substudy. CTC isolation and enumeration were centralized and performed using the CellSearch System (Veridex LLC, Raritan, NJ) in 7.5 mL of whole blood. Evaluation of KRAS status was performed retrospectively by the standard method used at each center. PFS and OS were analyzed by the Kaplan-Meier method according to CTC count and KRAS status. RESULTS Patients with < 3 CTC per 7.5 mL blood at baseline and KRAS wild-type tumors had a median PFS of 14.2 months compared with 6.2 months in patients with ≥ 3 CTCs and KRAS mutated tumors (P < .0001; hazard ratio, 3.0; 95% confidence interval, 1.8-5.2). Similar findings were observed for OS (28.9 and 13.7 months, respectively, P = .0004; hazard ratio 2.8; 95% confidence interval, 1.6-4.9). Multivariate analyses showed that CTC count ≥ 3 and KRAS status were the only independent prognostic factors for both PFS and OS. CONCLUSIONS This post hoc analysis showed that CTC count and KRAS status were independent prognostic factors for outcomes in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy. These factors should be taken into account in the design of future phase III trials.

Cisplatin and gemcitabine administered every two weeks in patients with locally advanced or metastatic urothelial carcinoma and impaired renal function

BACKGROUND Cisplatin-based combination chemotherapy is the mainstay of treatment for locally advanced or metastatic urothelial carcinoma. However, standard dose schedule of cisplatin cannot be used in patients with impaired renal function. We evaluated the safety and efficacy of gemcitabine and a split dose administration of cisplatin in patients with renal dysfunction. PATIENTS AND METHODS Patients with locally advanced or metastatic urothelial carcinoma with creatinine clearance between 35 and 59 ml/min received gemcitabine 2500 mg/m(2) and cisplatin 35 mg/m(2) on day 1 and day 15 for an every 28 day schedule. RESULTS Between March 2004 and November 2009, 38 patients were treated. Median creatinine clearance was 49 ml/min. Median number of cycles per patient was 3 (1-7). There were 15 partial responses (39%) and 12 patients had stable disease (31%). Median progression free survival and overall survival were 3.5 and 8.5 months (mo), respectively. Grade 3-4 haematological toxicities were: neutropenia 9%, anaemia 6% and thrombocytopenia 16%. No patient developed renal toxicity. CONCLUSIONS Biweekly gemcitabine and cisplatin is an active and feasible regimen in this subset of patients and could be an option for unfit patients. However, results seem not to be superior to those obtained with carboplatin based regimens in this population of patients.

Stage II Disease, Elderly Patients, Secondary Neoplasms, and the MOSAIC Trial

TO THE EDITOR: We congratulate Tournigand et al on the publication of the results of the post hoc exploratory study of patients with stage II disease and elderly patients in the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC). However, we would like to make some comments on certain aspects of the article. First and foremost, we are intrigued at the relevant delay in the publication of the results in 2012, taking into account that the cutoff date for analysis of survival was January 16, 2007. This suggests a follow-up that was not updated when compared to the previous publication. In fact, the publications present median follow-ups of 81.9 months and 80 months, respectively. Furthermore, when examining the 2010 American Society of Clinical Oncology meeting abstracts (abstracts 3522 and 3524) in detail, both the number of patients alive with relapse and the number of second cancers are identical to the data that were provided in the current report. Therefore, one could interpret that the current results were already available, at least when the 2009 article was published, and probably even before. Interestingly, in their report, the authors raise a relevant concern regarding chemotherapy-induced secondary neoplasms. To supplement this evidence, we want to add our personal experience with 139 patients with stage II or III disease who received adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) at our institution. With a median follow-up of 36 months, eight patients developed a second neoplasm. One of them, a 56-year-old man, developed an aggressive acute myeloblastic leukemia (therapy related [monosomy 7]), 18 months after initiation of FOLFOX4 as adjuvant chemotherapy. Another point of discussion is to what extent the change in age rangesisjustifiedintheauthors’mostrecentreport.Wethinkthattheage classificationshouldhavebeenthesameasitappearsinthetwopreviously published articles. As was shown, the survival hazard ratio was approximately 1.0 in patients with stage III disease and patients older than age 64 years inbotharticles.Thus, ifdatafromthe2009publicationdidnotshow a benefit from FOLFOX4 in patients older than age 65 years, and the results have not been updated, then it is difficult to argue that patients between age 65 and 69 years can obtain a benefit from oxaliplatin. Furthermore, we do not find justification for the inclusion of death as a result of other causes at time point 0 in the post–disease-free survival curves. If the idea is to consider the survival of patients after relapse, the fact that the curves have different starting points (because of this inclusion of death as a result of other causes) does not add anything. What is relevant is whether, once a patient presents with a relapse, his survival expectations differ from that of the other group. The fact that there is a 20% offset does not lead to solid conclusions. Finally, one third of patients with stage II disease had fewer than 10 nodes retrieved, which, according to the recommendations, is insufficient. Therefore, a certain self-criticism regarding surgical quality is lacking. Furthermore, we have observed heterogeneity in the definition of high risk in stage II disease according to the number of lymphatic nodes examined. In an American Society of Clinical Oncology 2010 meeting presentation, the limit of 12 nodes to define high-risk stage II disease was chosen; now the criterion has been changed to nine or fewer nodes.

Relationship of duration of androgen blockade and response to antiandrogen withdrawal: A retrospective study.

e15104 Background: Patients with progressive prostate cancer treated with androgen blockade, might achieve prostate-specific antigen (PSA) decline or stabilization after discontinuation of antiandrogen treatment. This phenomenon is called antiandrogen withdrawal response and is often associated with clinical improvement. METHODS PSA response of 170 patients from two different centers was retrospectively analyzed. Eligible patients had progressive prostate cancer during treatment with androgen blockade (orchiectomy or LHRH agonist plus antiandrogen). Patients were stratified according to Gleason grade (≤6 vs >6), stage at diagnosis (II, III, IV), type of antiandrogen (bicalutamide, flutamide or steroidal antiandrogens) and duration of treatment blockade (≤12 or >12 months). Clinical benefit (CB) was defined as a confirmed PSA decline ≥50% or stabilization for ≥3 months. RESULTS Median age was 71 years (range 48 - 91). One hundred forty-one patients had a Karnofsky performance status (K PS) ≥ 80%. Of the 170 patients, 108 (63.5%) had PSA progression after antiandrogen withdrawal and 62 (36.5%) had PSA stabilization or decline. No significant correlation between stage, Gleason grade or K PS and CB was found. Ninety-eight (57.6%) patients had previously received bicalutamide, 52 (30.6%) flutamide and 20 (11.8%) steroidal antiandrogens. CB after antiandrogen withdrawal was observed in 37.8% (37/98), 44.2% (23/52) and 10% (2/20) of patients in the group of bicalutamide, flutamide and steroidal antiandrogens respectively (p=0.024). Longer duration of antiandrogen blockade was associated with CB: 40.5% (53/131) of patients who had received more than 12 months of antiandrogen blockade vs 23.1% (9/39) among patients who had received ≤ 12 months (p=0.0478). Median duration of response was 7 months (range 3 - 52). CONCLUSIONS In patients with progressive prostate cancer, antiandrogen withdrawal may be a useful maneuver resulting, in some cases, in prolonged responses. According to this study, duration of androgen blockade treatment and use of non steroidal antiandrogen may predict a favorable response to antiandrogen withdrawal.

ALK chromosomal alterations in neuroendocrine tumors.

10585 Background: Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms containing biologically active peptides and amines in their cytoplasm. Anaplastic lymphoma kinase (ALK) translocation has recently emerged as a potent predictor of benefit for treatment with ALK inhibitors. The endpoint of this study was to analyze ALK translocations and gene copy number status in a series of neuroendocrine tumors and correlate these findings with clinico-pathological features. METHODS Paraffin-embedded specimens from gastroenteropancreatic (GEP) and lung neuroendocrine tumors from patients diagnosed between years 2004-2010 were retrospectively retrieved from the tumor bank at our Institution. ALK gene status was characterized by fluorescence in situ hybridization (FISH) with a break-apart ALK probe (Abbot Molecular Inc). Translocation and gene copy gain were defined as previously reported (Salido et al). FISH ALK-positive and a set of negative cases were evaluated by immunohistochemistry (ALK-1, Dako). Statistical analysis was carried to evaluate the association between ALK gene alterations and clinico-pathological features. This study was approved by the review board at our Institution. RESULTS One hundred and eleven neuroendocrine tumors were included in the study. In 42 cases the sample was insufficient/inconclusive FISH results, leaving a final number of 69 evaluable cases (43 GEP, 20 lung, 6 other). There was one GEP neuroendocrine tumor (appendix) with an EML4-ALK translocation in 15% of tumoral cells and one lung neuroendocrine tumor with an atypical ALK translocation in 60% of tumoral cells (unknown partner). Ten cases (7 GEP; 3 lung) showed an increase in ALK gene copy number (mean 5 copies; range: 3-10 copies) with the percentage of cells with ALK copy gain ranging between 18-65% (mean 36%). Immunohistochemistry revealed <10% of tumor cells with mild ALK staining in the specimen with EML4-ALK translocation. The low number of positive cases precluded the finding of statistical associations. CONCLUSIONS Although rare, ALK translocations are present in neuroendocrine tumors. This reveals a potential new indication for ALK inhibitors that merits further investigation.

Gemcitabine/cisplatin in patients with advanced bladder and impaired renal function: A retrospective analysis.

274 Background: A four-weekly regimen of gemcitabine and cisplatin (GEMCIS) has similar activity and is less toxic than MVAC in advanced bladder cancer. However, full-dose cisplatin in unfit patients with impaired renal function is contraindicated and other carboplatin-based schedules have been developed. We have previously reported the feasibility of GEMCIS in a biweekly schedule in unfit patients with renal impairment. Here we report a multicenter retrospective study of this biweekly regimen in patients with impaired renal function. METHODS Between January 2004 and October 2009, 40 patients with locally advanced nonsurgically resectable or metastatic bladder cancer and impaired renal function were included. Treatment consisted of gemcitabine 2500 mg/m2 on day 1 and cisplatin 35 mg/m2 on day 1, every 14 days. RESULTS Median age of the patients was 73 years (range: 51-82 years). Median IK was 80% (range: 60-100%). Mean creatinine clearance was 49 ml/min (range:37-59 ml/min). Eight patients had previously received chemotherapy with gemcitabine and/or platinum based therapy. Metastatic localizations were: 17 lymph nodes, 10 pulmonary, 10 bone, 7 liver, 12 pelvic and 1 central nervous system. The median number of cycles/patient was 6 (1-13). Out of 36 patients evaluable for response, there was one complete response, 14 partial responses (ORR: 42%; 95% CI 27-58%), 11 stabilizations and 10 progressive diseases. Hematologic toxicities were grade 1 anaemia in 15 patients, grade 2 in 8; grade 3 in 2; grade 3 neutropenia in 5 patients and grade 4 in 1 patient; grade 3 plaquetopenia in 3 patients. Nonhematologic toxicities were grade 1-2 vomiting in 2 patients. Two patients showed a grade 2 hepatic toxicity. Worsening of the renal function was observed in two patients. Alopecia grade 1-2 was seen in three patients. There was one toxic death related to metabolic acidosis.The median progression-free survival is 15 weeks. The median OS from first cycle of GEMCIS is 35 weeks and 1-year OS is 43% (St error 9%). CONCLUSIONS A two-weekly schedule of gemcitabine plus cisplatin is feasible, active, and generally well tolerated in an outpatient setting in unfit patients with poor renal reserve. No significant financial relationships to disclose.