Antonia Strippoli

Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer?

BACKGROUND The KRAS mutation is not responsible for all cases of resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC), and new predictive and prognostic factors are actively being sought. PATIENTS AND METHODS We retrospectively evaluated the efficacy of a cetuximab-containing treatment in 73 patients with mCRC according to KRAS and BRAF mutational status as well as PTEN, c-MET, and insulin-like growth factor receptor (IGF1R) expression. RESULTS Overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were significantly lower in patients with KRAS mutation than in patients with KRAS wild-type; among the population with KRAS wild-type, only 2 patients with BRAF mutations were found and neither of them achieved a response. No significant association was found between PTEN and clinical outcome. Compared with low/normal expression, c-MET overexpression significantly correlated with shorter mPFS and mOS: 3 vs. 5 months (P = .018) and 11 vs. 10 months (P = .037), respectively. In patients with high IGF1R expression, mOS was significantly longer than in those with low/normal expression (14 vs. 8 months; P = .015). CONCLUSION KRAS mutation significantly correlates with a worse outcome in patients treated with cetuximab, whereas no definitive inference can be drawn about the role of BRAF mutation and PTEN loss of expression. Instead, c-MET overexpression might represent a negative prognostic factor in mCRC and may have a role in resistance to anti-EGFR therapy. Interestingly, IGF1R overexpression seems a favorable prognostic factor in mCRC.

KRAS mutational status affects oxaliplatin-based chemotherapy independently from basal mRNA ERCC-1 expression in metastatic colorectal cancer patients

Background:In this study, we evaluated the possibility that KRAS mutational status might be predictive of oxaliplatin (OXA) efficacy. We also explored the role of excision repair cross complementing group-1 (ERCC-1).Methods:Ninety anti-epidermal growth factor receptor-naive advanced colorectal cancer patients were retrospectively analysed. In all patients KRAS mutational status was assessed. In 60 patients mRNA ERCC-1 expression was also investigated. Response rate (RR) and progression-free survival (PFS) after FOLFOX-6±bevacizumab were evaluated according to KRAS status and mRNA ERCC-1 expression.Results:Among 90 patients 47% wild-type (wt) and 53% mutated (mt) KRAS tumours were found. Response rate was 26% in the wt KRAS group, whereas it was 56% in the mt KRAS group; the difference is statistically significant in the total sample (P=0.008) and when only patients receiving FOLFOX-6±bevacizumab as first-line are considered (P=0.01). Progression-free survival was longer in mt than in wt KRAS patients over all patients (10 vs 8 months, respectively, P=0.001) and in those treated as first-line (10 vs 8 months, respectively, P=0.0069). Mt KRAS patients experienced a longer survival (24 vs 18 months; P=0.01). ERCC-1 mRNA expression was not found to correlate with FOLFOX activity in our analysis.Conclusion:Our results suggest that activating mutation of KRAS oncogene may predict response to OXA. Basal expression of ERCC-1 mRNA does not explain the high efficacy of FOLFOX-6 in mt KRAS patients.

Treatment Options for EGFR T790M-Negative EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer

The introduction of first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib and afatinib) for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC) has dramatically improved patients’ prognosis and quality of life (QoL). Unfortunately, after an initial and sometimes durable benefit from EGFR-TKI therapy, all patients with EGFR-mutant lung cancer eventually become resistant to the treatment and experience disease progression. In approximately 50% of these patients, genomic alterations in the EGFR kinase domain resulting in the mutant T790M are responsible for the resistance and this has led to the development of novel EGFR inhibitors active against mutant-T790M EGFR. The remaining 50% of patients with acquired resistance (AR) to EGFR-TKIs do not harbour the T790M mutation. In these cases, other mechanisms are involved in the development of AR such as perturbations of downstream pathways (e.g. K-RAS mutations), activation of alternative bypassing pathways (including c-Met, AXL, PIK3CA, BRAF), or histologic transformation. This review summarizes the main treatment strategies for this particular and heterogeneous group of “T790M-negative” patients.

ERCC1 expression affects outcome in metastatic pancreatic carcinoma treated with FOLFIRINOX: A single institution analysis

Introduction No clinically useful predictive factor has been yet identified for treatment of metastatic pancreatic cancer (mPC). It is noteworthy that FOLFIRINOX, despite its high toxicity, is effective only in some patients. We retrospectively analyzed expression of excision repair cross-complementing group-1 (ERCC1) - involved in the repair of platinum induced damage - in patients affected by mPC treated with FOLFIRINOX in order to evaluate its predictive role. Results FOLFIRINOX resulted more effective in patients with normal ERCC1 levels than in those with ERCC1 hyper-expression. Median progression free survival (PFS) was 11 vs. 4 months (HR 0.26; 95% CI 0.14-0.50; p<.0001), median overall survival (OS) 16 vs. 8 months (HR 0.23; 95% CI 0.12-0.46; p<.0001) and disease control rate (DCR) 93% vs. 50% (p=0.00006). The advantage was confirmed at univariate and multivariate analysis. Patients and Methods 71 patients with histologically proven mPC and treated with FOLFIRINOX as first-line therapy were considered eligible. mRNA ERCC1 expression was determined using RT-PCR analysis. Discussion ERCC1 might be an effective predictor of response to FOLFIRINOX in mPC. Patients overexpressing ERCC1 should be excluded by this often toxic therapy and referred to an alternative treatment.

ERCC1 Induction after Oxaliplatin Exposure May Depend on KRAS Mutational Status in Colorectal Cancer Cell Line: In Vitro Veritas

Introduction: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer (mCRC), but currently there are not valid predictors of response to this drug. In the control arms both of OPUS and PRIME studies Oxa seems more active in patients with mCRC with mutated (mt) KRAS than in those with wild type (wt) KRAS. Recently we have retrospectively confirmed this suggestion, therefore we have hypothesized that the mutational status of KRAS could influence the expression of ERCC1, one of the main mechanisms of Oxa resistance. Material and Methods: We used four cell lines of colorectal cancer: two KRAS wild type (wt) (HCT-8 and HT-29) and two KRAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test as well the ERCC1 levels before and after 24 h exposure to Oxa by Real-Time PCR. We silenced KRAS in a KRAS mt cell line (SW620LV) to evaluate the impact on Oxa sensitivity and ERCC1 levels. Lastly, ERCC1 was also silenced in order to confirm the importance of this protein as an Oxa resistance factor. Results: The KRAS mt cell lines resulted more sensitive to Oxa (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between KRAS mt and wt cell lines, however, after 24 h exposure to Oxa, only the wt KRAS lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). By silencing KRAS, sensitivity to Oxa was reduced in mt KRAS cell lines and this effect was associated with the acquisition of ability to induce ERCC1. Silencing of ERCC1, in turn, enhanced the sensitivity to Oxa in wt KRAS cell lines and restored sensitivity to Oxa in SW620LV cell line. Conclusion: KRAS mutated cell lines were more sensitive to Oxa. This feature seems secondary to the inability of these cells to induce ERCC1 after exposure to Oxa. Thus, KRAS mutational status might be a predictor of response to Oxa in CRC surrogating the cell ability to induce ERCC1.

Conversion Chemotherapy for Technically Unresectable Colorectal Liver Metastases: A Retrospective, STROBE-Compliant, Single-Center Study Comparing Chemotherapy Alone and Combination Chemotherapy With Cetuximab or Bevacizumab

Abstract The response rate of patients with unresectable liver-limited metastases of colorectal cancer can be improved by converting inoperable disease to operable disease. However, the benefits of conversion chemotherapy for survival are still controversial. Patients considered to have technically inoperable disease by a multidisciplinary team were retrospectively analyzed. Patients were stratified based on the treatment they received, into the chemotherapy only (G1), chemotherapy plus bevacizumab (G2), or chemotherapy plus cetuximab (G3) groups. The primary endpoint was the resection rate. The secondary endpoint was the overall survival (OS), according to both the treatment received and liver surgery status. In total, 104 patients were included: 30 in the G1, 39 in the G2, and 35 in the G3 groups. All G3 patients had the wild-type KRAS exon 2. The surgical resection rates for patients in the G1, G2, and G3 groups were 43.3% (13/30), 30.7% (12/39), and 51.4% (18/35), respectively. Disease-free survival did not show significant differences among the 3 groups. The median OS was 35.2 months in the G1, 28.8 months in the G2, and 42.1 months in the G3 (P = 0.25) groups. The OS was significantly higher in patients who underwent surgical resection than those who did not. The median OS was 28.4 months in patients who did not undergo resection, whereas it had not been reached after a median follow-up period of 37.5 months for patients who underwent surgical resection (events: 21/43). Our data confirmed that the conversion of initially inoperable disease to operable disease conferred a survival benefit, even in patients who relapsed after surgery. The addition of cetuximab to chemotherapy improved the objective response and resection rates, conferring a potential survival benefit even in patients whose diseases were not converted to operable disease, compared to chemotherapy alone or in combination with bevacizumab.

Maintenance hormonal and chemotherapy treatment in metastatic breast cancer: a systematic review.

Endocrine treatment is the first-line therapy in hormone-sensitive metastatic breast cancer while chemotherapy is the first option in tumors refractory to endocrine therapy and in hormone-negative disease. Optimal duration, efficacy and safety of a maintenance endocrine therapy or chemotherapy after an induction treatment are still a matter of debate. We performed a literature review to identify studies regarding maintenance hormonal and chemotherapy treatments in metastatic breast cancer. We analyzed data relating to efficacy (improvement of progression-free survival and overall survival) and safety (symptoms relief and quality of life [QoL]). Maintenance endocrine therapy could prolong progression-free survival with a better control of symptoms and improving QoL. Maintenance chemotherapy prolong the response to a previous treatment, worsening the QoL, except for metronomic capecitabine.

Unexpected side effect in mcrc: A care-compliant case report of regorafenib-induced hyperammonemic encephalopathy

Rationale: Regorafenib represents a treatment option in heavily pretreated patients affected by metastatic colorectal cancer (mCRC). Its safety profile is typical of small-molecule tyrosine-kinase inhibitors (TKIs) and most adverse events are manageable. Patient concerns: A 56 years-old Caucasian man affected by mCRC with normal hepatic reserve was treated with regorafenib as second-line treatment. After only 2 days of therapy, the patient presented to the emergency department due to impairment of both spatial and temporal orientation and motor function with bradylalia. Interventions: Serum ammonia level was 191 mmol/L, liver function tests and complete blood count were normal. Regorafenib was withheld and branched chain amino acids and lactulose were administered. Outcomes: Serum ammonia level returned within the normal range, but when regorafenib was restarted at a lower dose level, a new episode of acute confusion arised. Main lesson: Discontinuation of regorafenib after confirmation of hyperammonemia is strongly recommended; reintroduction of the therapy at lower doses after resolution of symptoms related to hyperammonemic encephalopathy has to be discouraged.

Preoperative therapy and long-term survival in gastric cancer: One size does not fit all

BACKGROUND The administration of perioperative chemotherapy represents the Western standard of care for patients with locally advanced gastric cancer. The aim of this study is to determine if the administration of the preoperative component of the perioperative regimen is beneficial in the entire population of patients with locally advanced gastric cancer. METHODS Seventy patients undergoing preoperative therapy were compared with 347 patients undergoing upfront gastrectomy. Survival analyses were conducted with Kaplan-Meier curves and Cox regression. Patients undergoing preoperative therapy or undergoing upfront gastrectomy were matched 1:1 using the propensity score matching (PSM) method, and a survival analysis was conducted on matched patients. A subgroup analysis was conducted by tumor location and Lauren histotype. RESULTS In patients undergoing preoperative therapy, factors significantly associated with survival were T and N downstaging, type of gastrectomy, resection status and Lauren histotype. Preoperative therapy was not significantly associated with survival (p = 0,761 before PSM and p = 0,519 after PSM). After PSM, the independent variables significantly associated with survival were type of gastrectomy, type of lymphadenectomy, R status and postoperative therapy. In the subgroup analysis, preoperative therapy demonstrated a selective association with the location of the tumor (p = 0,055) and with Lauren intestinal histotype (p = 0,002). CONCLUSIONS Preoperative therapy had a non-significant impact on survival in the entire population of gastric cancer patients. The advantage of preoperative therapy seems to be limited to patients with proximal tumors and an intestinal histology. Future studies should better evaluate the diverse response of the different phenotypes of gastric cancer to preoperative therapy.

The interference between oxaliplatin & anti-EGFR therapies: a different hypothesis to explain the ‘unexplainable’

This paper has been written because we have a differing idea concerning the suspected negative interference between oxaliplatin and anti-EGFR therapies in cancer patients. Several multicenter, randomized, controlled clinical trials investigated whether the efficacy of oxaliplatin-based chemotherapy is improved by the addition of anti-EGFR therapies in patients affected by KRAS wild-type advanced colorectal cancer. Results of these trials have produced puzzling findings, with some studies demonstrating improved survival and other studies showing no differences in overall survival between experimental and control arms. Moreover, a detrimental effect has been demonstrated in some settings. Nevertheless, the extent of this interaction remains uncertain. Some physicians proposed personal interpretations. This paper describes our hypothesis.