ABSTRACT
OBJECTIVE: Compassion is oriented towards perceiving and relieving suffering. Hence, its development is beneficial for mental health. Many interventions aimed at cultivating compassion in patients have been empirically supported. This meta-analysis analyses the effectiveness of compassion-focused therapy (CFT) in decreasing self-criticism, a vulnerability factor that has been related to several mental health problems, and in increasing self-soothing. METHODS: A literature search was conducted in the PsycInfo, Web of Science, Medline and Scopus databases, through which 7 controlled trials (N = 640) and 7 observational studies (N = 207) were retrieved. RESULTS: The results of the meta-analysis determine that CFT decreases the level of self-criticism and increases the ability to experience soothing. The size of the effect varies depending on the design of the study and the subscale of the test used to measure self-criticism (Forms of Self-Criticizing/Attacking and Self-Reassuring Scale). CONCLUSIONS: CFT has proven to be an effective intervention for reducing self-criticism. However, given that the number of studies is small and that only half of them are controlled trials, the results must be interpreted cautiously. More randomized controlled trials comparing CFT with other therapies are needed to determine the effect of this intervention on self-criticism with more scientific evidence.
Subject(s)
Empathy , Self-Assessment , Humans , Mental HealthSubject(s)
Chemotherapy, Adjuvant , Colonic Neoplasms , Liquid Biopsy , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Adjuvant/methods , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Colonic Neoplasms/therapy , Humans , Liquid Biopsy/methods , Neoplasm Staging , Retrospective StudiesABSTRACT
Drug resistance is an almost inevitable consequence of cancer therapy and ultimately proves fatal for the majority of patients. In many cases, this is the consequence of specific gene mutations that have the potential to be targeted to resensitize the tumor. The ability to uniformly saturate the genome with point mutations without chromosome or nucleotide sequence context bias would open the door to identify all putative drug resistance mutations in cancer models. Here, we describe such a method for elucidating drug resistance mechanisms using genome-wide chemical mutagenesis allied to next-generation sequencing. We show that chemically mutagenizing the genome of cancer cells dramatically increases the number of drug-resistant clones and allows the detection of both known and novel drug resistance mutations. We used an efficient computational process that allows for the rapid identification of involved pathways and druggable targets. Such a priori knowledge would greatly empower serial monitoring strategies for drug resistance in the clinic as well as the development of trials for drug-resistant patients.
Subject(s)
Drug Resistance, Neoplasm/genetics , Genome, Human , Mutation Accumulation , Mutation Rate , Cell Line, Tumor , Humans , Models, Genetic , Point MutationABSTRACT
An accurate profiling of the genomic landscape is mandatory to establish the best clinical and therapeutic approach for patients with solid malignancies. Moreover, tumor cells constantly adapt to external pressures-i.e., systemic treatment-with the selection and expansion of resistant subclones and the emergence of heterogeneous overlapping genomic alterations of resistance. The current standard for molecular characterization in cancer is the performance of a tissue tumor biopsy at the time of diagnosis and, when possible, a re-biopsy at the time of progression. However, tissue biopsy is not always feasible or practical and may underestimate tumor heterogeneity and clonal dynamics. Circulating DNA fragments carrying tumor-specific sequence alterations (circulating tumor DNA, ctDNA) are released from cancer cells into the bloodstream, representing a variable and generally small fraction of the total circulating cell-free DNA. Tumor genotyping in ctDNA (liquid biopsy) offers potential advantages versus the standard tumor tissue biopsy, including non-invasiveness and representation of molecular heterogeneity. Technical advances in sequencing platforms have led to dramatic improvements in variant detection sensitivity and specificity that allow for the detection and quantification of low levels of ctDNA. This provides valuable information on both actionable mutations and captures real-time variations in tumor dynamics. Liquid biopsy clinical applications include molecular diagnosis, determination of tumor load as a surrogate marker of early response, monitoring of mutations of resistance to targeted therapy and detection of minimal residual disease after cancer surgery. The aim of this chapter is to provide an overview of the biological rational and technical background of ctDNA analysis, as well as on the main clinical applications of liquid biopsy in dynamic treatment stratification in solid tumors. Special emphasis will be made on the current and potential benefits of the implementation of ctDNA in clinical practice, mainly in melanoma, lung, and colorectal cancer.
Subject(s)
Circulating Tumor DNA/genetics , Liquid Biopsy , Neoplasms/genetics , Neoplasms/therapy , Circulating Tumor DNA/analysis , Circulating Tumor DNA/blood , Humans , Mutation , Neoplasm, Residual/blood , Neoplasm, Residual/diagnosis , Neoplasm, Residual/genetics , Neoplasms/blood , Neoplasms/diagnosisABSTRACT
OBJECTIVES: This study aimed to examine the feasibility of running and evaluating a compassion-focused therapy (CFT) group adapted for acute inpatient settings, characterized by unpredictable lengths of admission, presentations, and diagnoses. DESIGN AND METHODS: This pilot project used a mixed methods design to assess the impact of offering CFT-informed group sessions on an acute inpatient unit. Pre- and post-session ratings of distress and calmness, and ratings of understanding and helpfulness, were gathered from participants over a 6-month period. Semi-structured interviews were conducted with four participants to gather their experience of the group. RESULTS: Fifty-seven complete sets of rating measures were generated from 82 participants recruited for the study (attrition rate 30%), from a total pool of 93 inpatients attending group sessions. Pre- to post-CFT session data highlighted a significant decrease in distress ratings and a significant increase in calmness ratings. A thematic analysis of four interviews identified themes relating to understanding compassion, experience of positive affect, and the experience of common humanity. CONCLUSIONS: This is the first attempt to explore the effects of a CFT-informed approach in acute mental health settings. These groups were well received by staff and patients, with some therapeutic impact despite being comparatively short and set against the background of a busy inpatient ward. These groups can be open and transdiagnostic, with stand-alone topics and practices having positive impacts on distress and calmness. Future studies need to focus on adapting content and pacing for this group of people based on ongoing feedback from participants.
Subject(s)
Empathy , Inpatients/psychology , Mental Disorders/therapy , Patient Education as Topic/methods , Psychotherapy, Group/methods , Aged , Feasibility Studies , Female , Humans , Interviews as Topic , Length of Stay , Male , Mental Disorders/diagnosis , Mental Disorders/psychology , Middle Aged , Pilot Projects , Program Evaluation , Qualitative Research , Treatment OutcomeABSTRACT
Emergence of acquired resistance limits the efficacy of the anti-EGFR therapies cetuximab and panitumumab in metastatic colorectal cancer. In the last decade, preclinical and clinical cohort studies have uncovered genomic alterations that confer a selective advantage to tumor cells under EGFR blockade, mainly downstream re-activation of RAS-MEK signaling and mutations in the extracellular domain of EGFR (EGFR-ECD). Liquid biopsies (genotyping of ctDNA) have been established as an excellent tool to easily monitor the dynamics of genomic alterations resistance in the blood of patients and to select patients for rechallenge with anti-EGFR therapies. Accordingly, several clinical trials have shown clinical benefit of rechallenge with anti-EGFR therapy in genomically-selected patients using ctDNA. However, alternative mechanisms underpinning resistance beyond genomics -mainly related to the tumor microenvironment-have been unveiled, specifically relevant in patients receiving chemotherapy-based multi-drug treatment in first line. This review explores the complexity of the multifaceted mechanisms that mediate secondary resistance to anti-EGFR therapies and potential therapeutic strategies to circumvent acquired resistance.
ABSTRACT
BACKGROUND: The impact of antibiotics (ATBs) on the risk of colorectal cancer (CRC) recurrence after curative resection remains unknown. METHODS: Using the French nation-wide database of cancer patients, all newly diagnosed non-metastatic CRC patients resected between 01/2012 and 12/2014 were included. The perioperative ATB intake (from 6 months before surgery until 1 year after) was classified according to the class, the period of use (pre- vs post-resection), the disease stage (localized and locally advanced), and the primary tumor location (colon and rectum/junction). The primary endpoint was the 3-year disease-free survival (DFS). The impact of ATB was assessed using time-dependent multivariate Cox models. RESULTS: A total of 35,496 CRC patients were included. Seventy-nine percent of patients had at least one ATB intake. Outpatient ATB intake after surgery was associated with unfavorable 3-year DFS. The ATBs associated with decreased 3-year DFS were cephalosporins, streptogramins, quinolones, penicillin A with beta-lactamase inhibitors, and antifungals with differential effects according to the primary tumor location and disease stage. CONCLUSION: These findings suggest that ATBs modulate the risk of recurrence after early CRC resection with a differential impact of the ATB classes depending on disease stage and tumor site.
ABSTRACT
BACKGROUND: Encorafenib plus binimetinib (EB) is a standard of care treatment for advanced BRAFV600-mutant melanoma. We assessed efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response. METHODS: E-BRAIN/GEM1802 was a prospective, multicenter, single arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression.Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%. RESULTS: The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After two months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial PFS and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grade 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%). CONCLUSION: Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.
ABSTRACT
PURPOSE: Chemotherapy plus anti-EGFR is standard first-line therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC), but biomarkers of early response are clinically needed. We aimed to define the utility of ctDNA to assess early response in patients with mCRC receiving first-line anti-EGFR therapy. EXPERIMENTAL DESIGN: Prospective multicentric study of tissue patients with RAS wt mCRC treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by NGS. Trunk mutations were assessed as surrogate marker of total tumor burden. RAS/BRAF/MEK/EGFR-ECD were considered mutations of resistance. ctDNA results were correlated with clinical outcome. RESULTS: One hundred patients were included. ctDNA was detected in 72% of patients at baseline and 34% at C3. Decrease in ctDNA trunk mutations correlated with progression-free survival (PFS; HR, 0.23; P = 0.001). RAS/BRAF were the only resistant mutations detected at C3. An increase in the relative fraction of RAS/BRAF at C3 was followed by an expansion of the RAS clone until PD, and was associated with shorter PFS (HR, 10.5; P < 0.001). The best predictor of response was the combined analysis of trunk and resistant mutations at C3. Accordingly, patients with "early molecular response" (decrease in trunk and decrease in resistant mutations) had better response (77.5% vs. 25%, P = 0.008) and longer PFS (HR, 0.18; P < 0.001) compared with patients with "early molecular progression" (increase in trunk and/or increase in resistant mutations). CONCLUSIONS: ctDNA detects early molecular response and predicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is recommended to integrate information on total disease burden and resistant mutations. See related commentary by Eluri et al., p. 302.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Rectal Neoplasms , Humans , Cetuximab , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Proto-Oncogene Proteins B-raf/genetics , Prospective Studies , Treatment Outcome , Colonic Neoplasms/drug therapy , Rectal Neoplasms/drug therapy , Liquid Biopsy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Mutation , Proto-Oncogene Proteins p21(ras)/geneticsABSTRACT
The management of localized rectal cancer requires a multidisciplinary approach to optimize outcomes, reduce morbidity and prevent under or overtreatments. While early stages may obtain benefit of local resections without any additional therapies, locally advanced rectal cancer becomes a challenge defining the better sequential strategy of surgery, radiotherapy and chemotherapy. The latest results of international phase III studies have positioned the total neoadjuvant therapy as a potential new standard of care in high risk rectal cancers, however, the best schedule is still not well defined.
Subject(s)
Neoplasms, Second Primary , Rectal Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy/methods , Humans , Neoadjuvant Therapy/methods , Neoplasm Staging , Rectal Neoplasms/pathology , Rectum/surgeryABSTRACT
Currently, the standard treatment for patients with localized colorectal cancer (CRC) includes surgical resection followed by adjuvant chemotherapy based on clinicopathological features. Recurrence risk stratification in those patients is of utmost importance to guide clinicians to avoid both under- and overtreatment. Recently, the concept of minimal residual disease (MRD) has emerged as the detection of circulating tumor DNA (ctDNA) carrying tumor-specific genomic or epigenomic alterations in the bloodstream of patients after surgery. Emerging studies described how the detection of MRD is a powerful prognostic biomarker to identify patients at higher risk of recurrence and who will potentially benefit the most from a systemic adjuvant treatment. Based on that unprecedented finding, several clinical trials involving stage II and III CRC patients are ongoing evaluating the impact of ctDNA guided treatment by escalating or deescalating adjuvant chemotherapy based on ctDNA MRD detection. This review provides a critical overview of current perspectives of liquid biopsy in early-stage CRC including technical, biological, and clinical key points, as well as ongoing ctDNA-based clinical trials that ultimately aim to improve clinical outcomes of patients with CRC.
ABSTRACT
PURPOSE: Total neoadjuvant treatment (TNT) is a valid strategy for patients with high-risk locally advanced rectal cancer (LARC). Biomarkers of response to TNT are an unmet clinical need. We aimed to determine the value of circulating tumor DNA (ctDNA) to predict tumor response, recurrence, and survival in patients with LARC treated with TNT. EXPERIMENTAL DESIGN: The GEMCAD 1402 was a phase II randomized, multicentric clinical trial that randomized 180 patients with LARC to modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) +/- aflibercept, followed by chemoradiation and surgery. Plasma samples were collected at baseline and after TNT within 48 hours before surgery (presurgery). An ultrasensitive assay that integrates genomic and epigenomic cancer signatures was used to assess ctDNA status. ctDNA results were correlated with variables of local tumor response in the surgery sample, local/systemic recurrence, and survival. RESULTS: A total of 144 paired plasma samples from 72 patients were included. ctDNA was detectable in 83% of patients at baseline and in 15% following TNT (presurgery). No association was found between ctDNA status and pathologic response. Detectable presurgery ctDNA was significantly associated with systemic recurrence, shorter disease-free survival (HR, 4; P = 0.033), and shorter overall survival (HR, 23; P < 0.0001). CONCLUSIONS: In patients with LARC treated with TNT, presurgery ctDNA detected minimal metastatic disease identifying patients at high risk of distant recurrence and death. This study sets the basis for prospective clinical trials that use liquid biopsy to personalize the therapeutic approach following TNT.
Subject(s)
Biomarkers, Tumor , Circulating Tumor DNA , Preoperative Period , Rectal Neoplasms/blood , Rectal Neoplasms/diagnosis , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Metastasis , Neoplasm Recurrence, Local , Neoplasm Staging , Prognosis , Rectal Neoplasms/mortality , Rectal Neoplasms/therapy , Treatment OutcomeABSTRACT
Immune checkpoints inhibitors (ICIs) have been a breakthrough, with unique response and survival patterns compared with chemotherapy for patients with advanced Mismatch Repair-deficient/Microsatellite instable (dMMR/MSI) colorectal cancer, but have shown disappointing results in Mismatch Repair-proficient/Microsatellite stable (pMMR/MSS) colorectal cancer. As up to 50% of patients harboring dMMR/MSI advanced cancers will ultimately progress after PD-1 blockade, biomarkers are needed to predict response/resistance to immunotherapy and to select patients for immunomodulating combination therapies. Patients with pMMR/MSS colorectal cancer present with distinct immune profiles compared to dMMR/MSI tumors, giving evidence of different immune escape mechanisms, which could be overcome through individualized immunotherapeutic strategies. In this review we discuss the latest developments in the field of immunotherapy for dMMR/MSI and pMMR/MSS colorectal cancers, and unresolved questions and considerations concerning the use of ICI therapies in this population. Future immunomodulation strategies based on biomarker selection (tumor mutational burden, Immunoscore®, mutational profile) are discussed.
Subject(s)
Colorectal Neoplasms/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Microsatellite Instability/drug effects , Humans , Immune Checkpoint Inhibitors/pharmacologyABSTRACT
IMPORTANCE: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. OBJECTIVE: To determine if continuous blockade of EGFR by Sym004 has survival benefit. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator's choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-type KRAS exon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. INTERVENTIONS: Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator's choice of treatment (arm C). MAIN OUTCOMES AND MEASURES: Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. RESULTS: A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n = 160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). CONCLUSIONS AND RELEVANCE: Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2013-003829-29.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Circulating Tumor DNA/blood , Colorectal Neoplasms/blood , Colorectal Neoplasms/drug therapy , Drug Resistance, Neoplasm , Patient Selection , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Circulating Tumor DNA/analysis , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/antagonists & inhibitors , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Survival Analysis , Treatment OutcomeABSTRACT
5-Fluorouracil (5-FU) is combined with folinic acid (FA) for enhancing its cytotoxic effects in the colon cancer chemotherapy treatment. Folinic acid has rarely been involved in hypersensitivity reactions. Here, we report a case of FA hypersensitivity in an adult patient initially attributed to oxaliplatin administered concurrently. A 56-year-old male patient diagnosed with colon cancer received twelve cycles of FOLFOX4, one cycle of FOLFIRI plus cetuximab and nine cycles of FOLFOX6 uneventful. At the tenth cycle of FOLFOX6 chemotherapy, after 15âminutes of starting the infusion of oxaliplatin and FA, the patient reported flushing, pruritus and abdominal pain and erythema and oedema developed over the face and thorax. After progression, FOLFIRI plus aflibercept was scheduled and another reaction occurred. At this time, FA was discontinued and the patient received another cycle consisted on irinotecan plus 5-FU without incidences. This episode of hypersensitivity reaction following FA infusion with no oxaliplatin empirically confirmed that the hypersensitivity reaction was secondary to FA. Clinicians should be aware of hypersensitivity reaction with FA, especially when FA is administered concomitantly with oxaliplatin, despite its lower risk to cause hypersensitivity reactions. Furthermore, the similar signs and symptoms associated to the hypersensitivity reactions of each agent, highlight the importance of having a specialised allergist team for to make a prompt diagnose of the causative agent in order to prevent patient harm and proceed properly without unnecessary delays in the scheduled chemotherapy treatments.
Subject(s)
Colonic Neoplasms/drug therapy , Drug Hypersensitivity , Leucovorin/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/complications , Drug Hypersensitivity/diagnosis , Fluorouracil/therapeutic use , Humans , Leucovorin/therapeutic use , Male , Middle Aged , Organoplatinum Compounds/therapeutic use , OxaliplatinABSTRACT
BACKGROUND: Approximately 50 % of malignant melanomas harbor activating point mutations in the BRAF gene. Typically, these mutations result in the substitution of the amino acid valine at codon 600 of the gene, and 90-95 % of mutations are either BRAF (V600E) or BRAF (V600K). Specific BRAF inhibitors such as dabrafenib and vemurafenib are the mainstays of treatment in patients with metastatic BRAF-mutant malignant melanomas. The third most common BRAF mutation is V600R, which also leads to increased BRAF signaling. Although evidence exists about the activity of dabrafenib and vemurafenib in patients with the BRAF (V600R) mutation, these patients have been systematically excluded from recent trials with targeted therapies. CASE PRESENTATION: Here, we report the positive results in terms of survival and quality of life obtained with dabrafenib in an 80-year-old Caucasian male patient with a Charlson Comorbidity Index of 8 diagnosed with metastatic malignant melanoma harboring the BRAF (V600R) mutation. Our patient was treated with dabrafenib for 7 months with minimal toxicity. We also report exploratory analyses of circulating tumor DNA during targeted treatment. Interestingly, the mutation was not detected after starting treatment and became detectable before radiological disease progression. CONCLUSIONS: Our report suggests that (1) a relevant benefit can be obtained with a BRAF inhibitor in real-world patients with a malignant melanoma harboring a BRAF (V600R) mutation, and that (2) circulating tumor DNA detection might be of help in assessing tumor burden in everyday clinical practice. The results reported here should encourage the inclusion of patients with BRAF (V600R)-mutated malignant melanomas in future prospective clinical trials with BRAF inhibitors.
Subject(s)
Antineoplastic Agents/therapeutic use , Ear Neoplasms/drug therapy , Imidazoles/therapeutic use , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Melanoma/drug therapy , Oximes/therapeutic use , Skin Neoplasms/drug therapy , Aged, 80 and over , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/secondary , Ear Neoplasms/genetics , Ear Neoplasms/pathology , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/secondary , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/secondary , Magnetic Resonance Imaging , Male , Melanoma/diagnostic imaging , Melanoma/genetics , Melanoma/secondary , Mutation , Proto-Oncogene Proteins B-raf/genetics , Quality of Life , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
OBJECTIVES: We aimed to determine the prevalence and partners of ROS1 rearrangements, to explore the correlation between FISH and IHC assays, and to investigate clinical implications of ROS1 copy number alterations (CNAs). METHODS: A total of 314 NSCLC patients were screened using ROS1 FISH break-apart probes. Of these, 47 surgical tumors were included in TMAs to analyze ROS1 heterogeneity assessed either by FISH and IHC, and chromosome 6 aneusomy. To characterize ROS1 partners, probes for CD74, EZR, SLC34A2 and SDC3 genes were developed. ROS1 positive FISH cases were screened also by IHC. RESULTS: Five patients were ROS1 positive (1.8%). We identified two known fusion partners in three patients: CD74 and SLC34A2. Four out of five ROS1 rearranged patients were female, never smokers and with adenocarcinoma histology. Rearranged cases were also positive by IHC as well. According to ROS1 CNAs, we found a prevalence of 37.8% gains/amplifications and 25.1% deletions. CONCLUSIONS: This study point out the high prevalence of ROS1 CNAs in a large series of NSCLC. ROS1 gains, amplifications and deletions, most of them due to chromosome 6 polysomy or monosomy, were heterogeneous within a tumor and had no impact on overall survival.
Subject(s)
Adenocarcinoma/genetics , Carcinoma, Large Cell/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Squamous Cell/genetics , DNA Copy Number Variations/genetics , Gene Rearrangement , Lung Neoplasms/genetics , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Large Cell/metabolism , Carcinoma, Large Cell/pathology , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Survival Rate , Tissue Array AnalysisABSTRACT
Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop EGFR ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival. In circulating cell-free tumour DNA of patients treated with anti-EGFR antibodies, RAS mutations emerge earlier than EGFR ECD variants. Subclonal RAS but not EGFR ECD mutations are present in CRC samples obtained before exposure to EGFR blockade. These data indicate that clonal evolution of drug-resistant cells is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies.