mutations are grouped in activating
-independent signaling as monomers (class 1-V600E) or as dimers (class 2-codons 597/601), and
-dependent with impaired kinase activity (class 3-codons 594/596). ...Although clinical, pathologic, and molecular features of
-mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes.
Data from 117 patients with
(92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540
wt mCRCs were included as control. IHC profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and progression-free survival were evaluated by Kaplan-Meier and log-rank test.
Class 3
-mutated mCRC was more frequently left sided (
= 0.0028), pN0 (
= 0.0159), and without peritoneal metastases (
= 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with
wt, was 2.38 95% confidence interval (CI), 1.61-3.54 for class 1, 1.90 (95% CI, 0.85-4.26) for class 2, and 0.93 (95% CI, 0.51-1.69) for class 3 (
< 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in
-mutated class 2 (
= 0.033) compared with class 3 cases.
For the first time, different clinical and pathologic features and outcome data were reported according to the three
mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.
The benefit of adjuvant chemotherapy has been clearly established in the adjuvant setting for node-positive colon cancer. A number of trials in the adjuvant setting have analyzed the efficacy of ...multiple-agent combinations, including irinotecan, oxaliplatin, bevacizumab and cetuximab. Only oxaliplatin added to fluorouracil/capecitabine has been shown to be superior beyond a fluropyrimidine alone in the adjuvant setting. As such, standard treatment options include fluorouracil (FU) or capecitabine with or without oxaliplatin. However, oxaliplatin is associated with cumulative dose-dependent neurotoxicity, characterized by distal or perioral paresthesias or dysesthesias; for this reason, in this review we discuss the results of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) trial. The IDEA trail is the largest prospective clinical trial ever conducted in colorectal cancer, wherein patients were treated with either 3 months or 6 months of adjuvant chemotherapy. In the era of cancer gene expression–based subtyping, the Colorectal Cancer Subtyping Consortium has proposed a four-subgroup molecular classification system for colorectal cancer, consisting of CMS1 (immune), CMS2 (canonical), CMS3 (metabolic) and CMS4 (mesenchymal). In this review, we present and analyze the available data on efficacy and toxicity of the combination regimen approved for treatment of resected colon cancer, and discuss the questions of when, how and how long we need to treat such patients.
Core tip: The benefit of adjuvant chemotherapy has been clearly established in the adjuvant setting for node-positive colon cancer. A number of trials in the adjuvant setting have analyzed the efficacy of multiple-agent combinations, including fluorouracil, capecitabine, irinotecan, oxaliplatin, bevacizumab and cetuximab. In this review, we present and analyze the available data on efficacy and toxicity of the combination regimen approved for treatment of resected colon cancer, and discuss the questions of when, how and how long we need to treat such patients.
In the last few years, significant advances in molecular biology have provided new therapeutic options for colorectal cancer (CRC). The development of new drugs that target the immune response to ...cancer cells seems very promising and has already been established for other tumor types. In particular, the use of immune checkpoint inhibitors seems to be an encouraging immunotherapeutic strategy. Areas covered: In this review, the authors provide an update of the current evidence related to this topic, though most immunotherapies are still in early-phase clinical trials for CRC. To understand the key role of immunotherapy in CRC, the authors discuss the delicate balance between immune-stimulating and immune-suppressive networks that occur in the tumor microenvironment. Expert opinion: Modulation of the immune system through checkpoint inhibition is an emerging approach in CRC therapy. Nevertheless, selection criteria that could enable the identification of patients who may benefit from these agents are necessary. Furthermore, potential prognostic and predictive immune biomarkers based on immune and molecular classifications have been proposed. As expected, additional studies are required to develop biomarkers, effective therapeutic strategies and novel combinations to overcome immune escape resistance and enhance effector response.
Background
Angiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are ...available regarding the efficacy of cabozantinib following immunotherapy.
Objective
To describe the outcome of cabozantinib in patients previously treated with immunotherapy.
Patients and methods
Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity.
Results
Eighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (
p
< 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3–14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up.
Conclusions
Cabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies.
Purpose
BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored ...survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations, with the aim to identify any predictive factors of response to targeted-based therapy.
Methods
A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted.
Results
We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%,
p
= 0.016), undifferentiated (71.4% v 44.0%,
p
= 0.004), KRAS wt (90.5% v 38.2%,
p
< 0.001), and MSI-H (41.7% v 16.2%,
p
= 0.019) tumors, with synchronous (52.4% v 31.5%,
p
= 0.018) and peritoneal metastases (38.1% v 22.4%,
p
= 0.003). Median overall survival (OS) was 16 v 27 months in BRAF mutant and BRAF wt (
P
= 0.020). In first-line setting, BRAF-mutant showed a 2ys OS of 80% in clinical trials, 32% in anti-VEGF, 14% in epidermial growth factor receptor (EGFR), and 0% in chemotherapy alone regimens (
P
= 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted therapy administered. However, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28 months,
P
= 0.005 in BRAF mutant v BRAF wt, respectively)
.
Conclusions
Our study demonstrated that BRAF status makes the difference in treatment’s outcome. Therefore, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis.
With the introduction of immune checkpoint inhibitors (ICIs) and next-generation vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFR–TKIs), the survival of patients with ...advanced renal cell carcinoma (RCC) has improved remarkably. However, not all patients have benefited from treatments, and to date, there are still no validated biomarkers that can be included in the therapeutic algorithm. Thus, the identification of predictive biomarkers is necessary to increase the number of responsive patients and to understand the underlying immunity. The clinical outcome of RCC patients is, in fact, associated with immune response. In this exploratory pilot study, we assessed the immune effect of TKI therapy in order to evaluate the immune status of metastatic renal cell carcinoma (mRCC) patients so that we could define a combination of immunological biomarkers relevant to improving patient outcomes. We profiled the circulating levels in 20 mRCC patients of exhausted/activated/regulatory T cell subsets through flow cytometry and of 14 immune checkpoint-related proteins and 20 inflammation cytokines/chemokines using multiplex Luminex assay, both at baseline and during TKI therapy. We identified the CD3+CD8+CD137+ and CD3+CD137+PD1+ T cell populations, as well as seven soluble immune molecules (i.e., IFNγ, sPDL2, sHVEM, sPD1, sGITR, sPDL1, and sCTLA4) associated with the clinical responses of mRCC patients, either modulated by TKI therapy or not. These results suggest an immunological profile of mRCC patients, which will help to improve clinical decision-making for RCC patients in terms of the best combination of strategies, as well as the optimal timing and therapeutic sequence.
Background: Although most of the analyses included transverse colon cancers (TCC) among right colon cancer (RCC), it is not completely clear if they present total similarities with RCC or if they ...have their specific features. Therefore, we present an observational study to evaluate clinicopathological characteristics and survival data of patients with TCC. Methods: We retrospectively reviewed 450 RCC, of whom 97 stages I–IV TCC were included in this multicenter study; clinicopathological and molecular parameters were analyzed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: Most of TCC cases were male (61%), with ≤70 years old (62%), and good performance status (ECOG PS 0, 68%). According to WHO classification, 41 (49%) and 40 (48%) tumors were classified as well to moderate and poorly/undifferentiated respectively, regardless of mucinous component (30%). About molecular data, 8 (26%), 45 (63%), and 14 (24%) were MSI-H, KRAS wild-type, and BRAF V600E mutant, respectively. With a median follow-up of 34 months, there were 29 and 50 disease recurrences and deaths respectively. Charlson comorbidity index ≥5 was a significant prognostic factor for DFS (HR = 7.67, 95% CI 2.27–25.92). Colon obstruction/perforation (HR = 2.65, 95% CI 1.01–7.01), and BRAF mutant (HR = 3.03, 95% CI 0.97–9.50) cases showed a worst, despite not statistically significant, DFS. Whereas for OS, at the multivariate model, only tumor grade differentiation (HR = 5.26, 95% CI 1.98–14.01) and BRAF mutation status (3.71, 95% CI 1.07–12.89) were independent prognostic factors. Conclusions: Poorly/undifferentiated tumor grade and BRAF V600E mutation are independent prognostic factors for OS in TCC. Further prospective clinical trials are needed to better define TCC treatment in order to improve patient outcome.
Study Type – Prognosis (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
Primary renal synovial sarcoma is a very rare renal neoplasm. Since 2000, when this ...tumour was first described, only case reports have been published in the medical literature.
This study is the first to describe the clinical and pathological features of primary renal synovial sarcoma and it found a relationship between these characteristics. Median overall and disease‐free survival were reported, and the risk of relapse for patients with non‐metastatic disease at diagnosis was found to be 36%. Different histological sub‐types, also described in other synovial sarcomas, were found in primitive renal tumours and directly related to tumour extension at diagnosis, different patterns of immunohistochemical stain and genetic alterations.
OBJECTIVE
•
To describe, for the first time, the clinical characteristics of primary renal synovial sarcoma (SS) and to examine the association of histological features with the expression of immunohistochemical markers.
PATIENTS AND METHODS
•
We collated published data on all cases of primary renal SS, from its first description in 2000 to September 2011.
•
Data on clinical and pathological characteristics were extracted and used to create a database.
•
Disease‐free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan–Meier method with Rothman's 95% confidence intervals (CIs) and compared across the groups using the log‐rank test.
•
The associations between tumour extension and histological features were evaluated using the non‐parametric Spearman rank test. A chi‐squared test was used to assess the differences between groups.
RESULTS
•
In the overall cohort, the median OS was 48 months (95% CI, 14.1–81.9).
•
Cox analysis showed that the risk of death at diagnosis was greatly increased in patients with metastatic disease compared with those with non‐metastatic disease (hazard ratio HR: 343.9, 95% CI, 2.8–42 000; P= 0.017).
•
The median DFS was 33.0 months (95% CI, 16.8–49.2), and patients who develop metastatic disease have a very poor prognosis with a median survival of 6 months (95% CI, 5.1–6.9).
•
Microscopic features were monophasic, biphasic and poorly differentiated synovial sarcoma in 76, 16 and 8% of patients, respectively.
•
Significant differences in expression of immunohistochemical markers or genetic mutation were found between different subtypes.
CONCLUSIONS
•
Despite its retrospective nature, this study shows that renal SS comprises different histological subtypes, which are characterized by specific immunohistochemical stains and by specific translocations.
•
When diagnosed at metastatic stage, the prognosis was very poor compared with that for non‐metastatic disease, even though one out of three patients with non‐metastatic disease had disease relapse.
•
Cooperative efforts and publication of cases with adequate follow‐up are necessary to better define prognosis and therapeutic strategies for this rare disease.
Abstract only
3536
Background: FOLFOXIRI/bevacizumab is a valuable upfront option in mCRC based on results of phase III TRIBE and TRIBE2 studies: 1187 pts aged 18–70 years with ECOG performance ...status (PS) ≤ 2 or between 71–75 years with an ECOG PS of 0 were randomized to receive first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI in TRIBE and mFOLFOX6 in TRIBE2)/bevacizumab. Here, we aimed at assessing the effect of the intensification of the upfront chemotherapy (triplet versus doublet) in terms of safety and efficacy in pts aged < 70 versus 70-75. Methods: Subgroup analyses for ORR, PFS, G3/4 overall adverse events (AEs), chemo-related and bevacizumab-related AEs were performed according to baseline age. Results: 182 (15%) out of 1187 pts were 70-75 years old (97 in the FOLFOXIRI/bevacizumab and 85 in the doublets/bevacizumab arms). The benefit provided by the intensification of the upfront chemotherapy was independent of the age subgroup in terms of both ORR (p for interaction = 0.684) and PFS (p for interaction = 0.634). The risk of overall and chemo-related G3/4 AEs was increased with the triplet independently of age (p for interaction = 0.736 and 0.790), while no difference in bevacizumab-related AEs was observed in both subgroups (p for interaction = 0.566). In the overall population, as compared to younger pts, those aged 70-75 were more susceptible to overall G3/4 AEs (70% vs 57%, p = 0.001). In the FOLFOXIRI/bevacizumab arm a higher incidence of G3/4 diarrhea (27% vs 17%, p = 0.016) and febrile neutropenia (16% vs 6% p = 0.001) and a lower incidence of all grade nausea (51% vs 65%, p = 0.009) and vomiting (26% vs 44% p = 0.001) were reported among elderly pts. Conclusions: The activity and efficacy of FOLFOXIRI/bevacizumab are confirmed among selected pts between 70 and 75 years old, with a relative increase in the risk of chemo-related AEs similar to that of younger pts. However, elderly pts are more susceptible to experience AEs independently of the treatment arm. Considering the increased incidence of febrile neutropenia and diarrhea with FOLFOXIRI/bevacizumab, the use of G-CSF as primary prophylaxis or an initial dose reduction of irinotecan and 5-fluorouracil might be considered in this population.
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