Therapies for cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa: a systematic review of 157 cases.

BACKGROUND: Invasive cutaneous squamous cell carcinomas (cSCC) are a leading cause of death in recessive dystrophic epidermolysis bullosa (RDEB), a rare blistering genodermatosis. Outcomes of RDEB-cSCC therapies have primarily been described in case reports. Systematic studies are scarce. This systematic review aims to assess the pathophysiology, clinical characteristics, and outcomes of RDEB-cSCCs, with a focus on results and mechanisms of recent immunotherapies and anti-EGFR treatments. RESULTS: A systematic literature search of epidermolysis bullosa and cSCC was performed in February 2024, using PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and EudraCT databases. Cases with administration of systematic therapies and unpublished outcomes regarding death were tracked with corresponding authors. Data extraction and risk of bias assessment was performed by two independent reviewers. Of 1132 references in the original search, 163 relevant articles were identified, representing 59 case reports, 7 cohort studies, 49 abstracts, 47 in-vitro/in-vivo experiments, and 1 bioinformatic study. From these, 157 cases of RDEB-cSCCs were included. The majority of RDEB-cSCCs were well-differentiated (64.1%), ulcerated (59.6%), and at least 2 cm in size (77.6%), with a median age at diagnosis of 30 years old (range 6-68.4). Surgery was the primary form of treatment (n = 128), followed by chemotherapy and radiotherapy. Anti-EGFR therapy and immunotherapy was also reported beginning in 2009 and 2019, respectively. Survival time from first cSCC diagnosis to death was available in 50 cases. When stratified by their treatment regimen, median survival time was 1.85 years (surgery + chemotherapy, n = 6), 2 years (surgery only, n = 19), 4.0 years (+ anti-EFGR therapy, n = 10), 4 years (surgery + radiotherapy, n = 9), 4.6 years (+ immunotherapy, n = 4), and 9.5 years (surgery + chemotherapy + radiotherapy; n = 2). Treatment-related adverse events were primarily limited to impaired wound healing for immunotherapies and nausea and fatigue for anti-EGFR therapies. CONCLUSIONS: Despite the challenges of a limited sample size in a rare disease, this systematic review provides an overview of treatment options for cSCCs in RDEB. When surgical treatment options have been exhausted, the addition of immunotherapy and/or anti-EGFR therapies may extend patient survival. However, it is difficult to attribute extended survival to any single treatment, as multiple therapeutic modalities are often used to treat RDEB-cSCCs.

Combining Anti-epidermal Growth Factor Receptor (EGFR) Therapy with Immunotherapy in Metastatic Colorectal Cancer (mCRC).

INTRODUCTION: Monoclonal antibodies binding the EGFR, such as cetuximab and panitumumab, have been extensively used as targeted therapy for the treatment of mCRC. However, in clinical practice, it has been found that these treatment options have some limitations and fail to fully exploit their immunoregulatory activities. Meanwhile, because of the limited effects of current treatments, immunotherapy is being widely studied for patients with mCRC. However, previous immunotherapy trials in mCRC patients have had unsatisfactory outcomes as monotherapy. Thus, combinatorial treatment strategies are being researched. AREAS COVERED: The authors retrieved relevant documents of combination therapy for mCRC from PubMed and Medline. This review elaborates on the knowledge of immunomodulatory effects of anti-EGFR therapy alone and in combination with immunotherapy for mCRC. EXPERT OPINION: Although current treatment options have improved median overall survival (OS) for advanced disease to 30 months, the prognosis remains challenging for those with metastatic disease. More recently, the combination of anti-EGFR therapy with immunotherapy has been shown activity with complementary mechanisms. Hence, anti-EGFR therapy in combination with immunotherapy may hold the key to improving the therapeutic effect of refractory mCRC.

The Impact of Sidedness on the Efficacy of Anti-EGFR-Based First-Line Chemotherapy in Advanced Colorectal Cancer Patients in Real-Life Setting-A Nation-Wide Retrospective Analysis (RACER).

Anti-EGFR antibodies combined with chemotherapy doublets are a cornerstone of the upfront treatment of colorectal cancer. RAS and BRAF mutations are established negative predictive factors for such therapy. The primary tumour located in the proximal colon has recently emerged as another negative predictive factor. We have conducted a retrospective multicentre study to collect data on real-world population characteristics, practice patterns, and outcomes in patients with metastatic colorectal cancer treated in a first-line setting with either cetuximab or panitumumab in combination with either FOLFOX or FOLFIRI chemotherapy. The presented analysis focuses on the impact of the primary tumour location. 126 of 842 patients analysed (15.0%) had proximal primary. It was associated with a lower BMI at diagnosis, mucinous histology, and peritoneal metastases. It was also associated with inferior treatment outcomes in terms of response ratio: 59.4% vs. 74.22% (odds ratio [OR] 0.51, 95% CI 0.33-0.78, p = 0.010), and median depth of response: -36.7% vs. -50.0% (p = 0.038). There was only a borderline non-significant trend for inferior PFS in patients with proximal tumours. OS data was incomplete. The presented analysis confirms the negative impact of tumour sidedness on the efficacy of an upfront anti-EGFR-chemotherapy combination and provides valuable data on real-world population characteristics.

LM02 trial Perioperative treatment with panitumumab and FOLFIRI in patients with wild-type RAS, potentially resectable colorectal cancer liver metastases-a phase II study.

Background: Twenty percent of colorectal cancer liver metastases (CLMs) are initially resectable with a 5-year survival rate of 25%-40%. Perioperative folinic acid, 5-fluorouracil, oxaliplatin (FOLFOX) increases progression-free survival (PFS). In advanced disease, the addition of targeting therapies results in an overall survival (OS) advantage. The aim of this study was to evaluate panitumumab and FOLFIRI as perioperative therapy in resectable CLM. Methods: Patients with previously untreated, wild-type Rat sarcoma virus (RAS), and resectable CLM were included. Preoperative four and postoperative eight cycles of panitumumab and folinic acid, 5-fluorouracil, irinotecan (FOLFIRI) were administered. Primary objectives were efficacy and safety. Secondary endpoints included PFS and OS. Results: We enrolled 36 patients in seven centers in Austria (intention-to-treat analyses, 35 patients). There were 28 men and seven women, and the median age was 66 years. About 91.4% completed preoperative therapy and 82.9% underwent liver resection. The R0 resection rate was 82.7%. Twenty patients started and 12 patients completed postoperative chemotherapy. The objective radiological response rate after preoperative therapy was 65.7%. About 20% and 5.7% of patients had stable disease and progressive disease, respectively. The most common grade 3 adverse events were diarrhea, rash, and leukopenia during preoperative therapy. One patient died because of sepsis, and one had a pulmonary embolism grade 4. After surgery, two patients died because of hepatic failure. Most common grade 3 adverse events during postoperative therapy were skin toxicities/rash and leukopenia/neutropenia, and the two grade 4 adverse events were stroke and intestinal obstruction. Median PFS was 13.2 months. The OS rate at 12 and 24 months were 85.6% and 73.3%, respectively. Conclusions: Panitumumab and FOLFIRI as perioperative therapy for resectable CLM result in a radiological objective response rate in 65.7% of patients with a manageable grade 3 diarrhea rate of 14.3%. Median PFS was 13.2 months, and the 24-month OS rate was 73.3%. These data are insufficient to widen the indication of panitumumab from the unresectable setting to the setting of resectable CLM.

Clinicopathological Profiles Associated with Discordant RAS Mutational Status between Liquid and Tissue Biopsies in a Real-World Cohort of Metastatic Colorectal Cancer.

We aimed to identify common mCRC profiles associated with a discordant mutational status of RAS between the standard of care (SoC) tumour tissue tests and ctDNA tests to understand ctDNA detection and improve treatment responses. This was a multicentre, retrospective and prospective study. A total of 366 Spanish mCRC patients were independently recruited. BEAMing ddPCR technology was employed to detect ctDNA RAS mutations, and logistic regression analyses were performed to investigate clinicopathological factors associated with discordance. The highest concordance ratios were observed in profiles with multiple metastatic sites when the liver was present (89.7%; 95% CI 84.8-93.2), profiles with synchronous disease without primary tumour resection (90.2%; 95% CI 83.6-94.3) and profiles with mCRC originating in the left colon (91.3%; 95% CI 85.0-95.0). Metachronous disease originating in the right colon (OR = 6.1; 95% CI 1.7-26.5; p-value = 0.006) or rectum (OR = 5.0; 95% CI 1.5-17.8; p-value = 0.009) showed the highest probability of discrepancies. Primary tumour resection and a higher frequency of single metastases in the peritoneum or lungs in these patients were associated with reduced plasmatic mutation allele fractions (MAFs) and an increased probability of showing false-negative genotypes. Additional testing of patients with mCRC originating in the right colon or rectum with a single non-mutated ctDNA test is advised before the choice of therapy.

Evaluation of the Prognostic Value of Low-Frequency KRAS Mutation Detection in Circulating Tumor DNA of Patients with Metastatic Colorectal Cancer.

KRAS mutation in tumor tissue is a well-known predictor of resistance to the treatment of anti-EGFR antibodies in metastatic colorectal cancers (mCRC). However, the prognostic value of low-frequency plasma circulating tumor DNA (ctDNA) KRAS mutation in predicting treatment resistance in pretreated mCRC patients remains controversial. This study retrospectively reviewed the clinical course, including response to anti-EGFR and anti-VEGF therapies, and changes in serum tumor marker levels along with image studies in mCRC patients with <1.5% KRAS mutations detected in plasma ctDNA by next-generation sequencing (NGS) at a single center in Taiwan. We identified six pretreated mCRC patients with low-frequency KRAS G12V/G12D/G12S/G13D mutations (variant allele frequency 0.26~1.23%) in plasma ctDNA. Co-occurring low-frequency ctDNA mutations in APC, TP53, MAP2K1, KEAP1, or CTNNB1 were also detected. Although all six patients had treatment adjustments within one month after the ctDNA genetic test, image-evident tumor progression was noted in all patients within a median of 4 months afterwards. Re-challenge therapy with a combination of anti-EGFR, anti-VEGF, and FOLFIRI chemotherapy was found to be ineffective in a patient with 0.38% KRAS G12D mutation in baseline ctDNA. Our study suggests that the detection of low-frequency KRAS mutations in ctDNA could be used as a predictor of treatment response in mCRC patients.

Optimal maintenance strategy following FOLFOX plus anti-EGFR induction therapy in patients with RAS wild type metastatic colorectal cancer: An individual patient data pooled analysis of randomised clinical trials.

BACKGROUND: Anti-EGFR antibodies plus doublet chemotherapy is the standard of care in RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No phase-3 level of evidence is available to guide treatment de-escalation after anti-EGFR-based first-line. Several randomised clinical trials investigated de-intensification strategies with 5-fluorouracil/leucovorin (5-FU/LV) and/or anti-EGFR. METHODS: We performed an individual patient data pooled analysis of Valentino, Panama, MACRO-2, COIN-B trials including RAS wild-type mCRC patients who received first-line therapy with FOLFOX plus panitumumab or cetuximab followed by pre-specified maintenance strategy. Only patients who started maintenance according to the assigned arm were included. Patients were categorised by type of maintenance (i.e. 5-FU/LV, anti-EGFR or 5-FU/LV + anti-EGFR). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of maintenance; toxicity was evaluated for the maintenance treatment period. RESULTS: A total of 518 patients were included in the pooled analysis. Overall, 123, 185 and 210 patients received maintenance with 5-FU/LV, anti-EGFR, 5-FU/LV + anti-EGFR, respectively. Median PFS was 5.6, 6.0 and 9.0 (P = 0.009) and OS was 25.7, 24.0 and 28.0 months (P = 0.134) in 5-FU/LV, anti-EGFR and 5-FU/LV + anti-EGFR arms, respectively. Monotherapy maintenance (either 5-FU/LV or anti-EGFR) was inferior to combination in terms of PFS (hazard ratios [HR] 1.26, P = 0.016) and non-significantly trending also in OS (HR 1.20, P = 0.111). An increase of overall any grade and grade ≥ 3 AEs and selected AEs was reported in combination compared to either 5-FU/LV or anti-EGFR arms. CONCLUSIONS: This pooled analysis including four randomised phase II supports the use of 5-FU/LV plus anti-EGFR as the preferred maintenance regimen. Data provide rational for a more individualised maintenance treatment approach based on tumour and patients features.

Health-related quality of life in patients with RAS wild-type metastatic colorectal cancer treated with fluorouracil and folinic acid with or without panitumumab as maintenance therapy: a prespecified secondary analysis of the PanaMa (AIO KRK 0212) trial.

BACKGROUND: The PanaMa trial demonstrated significant benefit in progression-free survival with the addition of panitumumab (Pmab) to fluorouracil and folinic acid (FU/FA) as maintenance therapy following first-line induction therapy with FOLFOX/Pmab in patients with RAS wild-type metastatic colorectal cancer. Here, we report health-related quality of life (HRQOL) analyses from the PanaMa trial. METHODS: HRQOL outcomes were evaluated using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at every cycle of therapy until disease progression/death. HRQOL outcomes were mean and individual changes in EORTC QLQ-C30 from baselines (before induction therapy and before maintenance therapy) to each cycle of treatment. Comparative analyses were performed by randomisation status and treatment arm for induction- and maintenance-therapy, respectively. The trial is registered with clinicaltrials.gov (NCT01991873). RESULTS: At least one HRQOL questionnaire was completed by a total of 349/377 (93%) patients who received induction therapy, and by 237/248 (96%) patients who were randomised and received maintenance therapy. During induction therapy, most HRQOL dimensions remained stable or showed improvement, while appetite loss and diarrhoea significantly deteriorated. During maintenance therapy, HRQOL dimensions remained stable, while those that deteriorated during induction therapy showed significant improvement, without significant differences between the treatment arms. CONCLUSION: Maintenance therapy improves HRQOL dimensions that initially deteriorated during induction therapy while stabilising HRQOL in other dimensions. The addition of Pmab to FU/FA as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer prolongs progression-free survival without negative impact on HRQOL.

Novel Insights of Anti-EGFR Therapy in HNSCC: Combined with Immunotherapy or Not?

PURPOSE OF REVIEW: The efficacy of anti-EGFR therapy is still unfavorable in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) patients. Disorder of antitumor immunity and aberrantly expressed checkpoint biomarkers had been validated to involve anti-EGFR therapy tolerance and efficacy. Here we review the immunomodulation of anti-EGFR therapy in the tumor immune microenvironment (TIME) of HNSCC and assist clinicians in finding the potential strategies to rescue anti-EGFR tolerance therapy in the era of immunotherapy for HNSCC. RECENT FINDINGS: Anti-EGFR therapy, especially cetuximab, was validated to induce the innate and adaptive immune responses of HNSCC patients. It is mainly through inducing natural killer (NK) cells mediating antibody-dependent cell-mediated cytotoxicity (ADCC), recruiting multiple tumor-infiltrating immune cells, and finally remodeling the TIME. Moreover, mountains of preclinical models and clinical trials revealed that combining anti-EGFR agents with immunotherapy could enhance the antitumor effectiveness in HNSCC. Anti-EGFR therapy may usher in another dawn in the treatment of patients with HNSCC through combination with immunotherapy. We offer an overview of the ongoing efforts to make out the immunomodulation of the EGFR pathway in both innate and adaptive immune responses; update the constant preclinical models and clinical trials for the combination of anti-EGFR and immunotherapy in HNSCC; and finally evaluate the efficacy and advantages of the combination therapeutic strategies in clinical use.

Overview of predictive and prognostic biomarkers and their importance in developing a clinical pharmacology treatment plan in colorectal cancer patients.

INTRODUCTION: Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide. Although overall survival for CRC patients has improved with earlier screening, survival continues to vary substantially across stages. Also, while the introduction of targeted therapies, including VEGF and EGFR inhibitors, has contributed to improving survival, better tools are needed to optimize patient selection and maximize therapeutic benefits. Emerging biomarkers can be used to guide pharmacologic decision-making, as well as monitor treatment response, clarify the need for adjuvant therapies, and indicate early signs of recurrence. This is a narrative review examining the current and evolving use of predictive and prognostic biomarkers in colorectal cancer. AREAS COVERED: Areas covered include mutations of the MAPK (KRAS, BRAF) and HER2 pathways and their impacts on treatment decisions. In addition, novel methods for assessing tumor mutations and tracking treatment responses are examined. EXPERT OPINION: The standard of care pathway for staging, and treatment selection and surveillance, of CRC will expand to include novel biomarkers in the next 5 years. It is anticipated that these new biomarkers will assist in decision-making regarding selection of targeted therapies and, importantly, in risk stratification for treatment decisions in patients at high risk for recurrence.

Phase II Single-Arm Study of Palbociclib and Cetuximab Rechallenge in Patients with KRAS/NRAS/BRAF Wild-Type Colorectal Cancer.

BACKGROUND: Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC. METHODS: We designed a single-arm, Simon's 2-stage, phase II trial of cetuximab and palbociclib in KRAS-WT mCRC treated with ≥2 prior lines of therapy. We report here on cohort B rechallenging patients with anti-EGFR-based therapy who had disease control of at least 4 months on prior anti-EGFR therapy. Primary endpoint was disease control rate (DCR) at 4 months. RESULTS: Ten evaluable patients were enrolled in this cohort. The 4-month DCR was 20%, which did not fulfill the prespecified 4-month DCR rate to continue. Median progression-free survival was 1.8 months and median overall survival was 6.6 months. Three patients had stable disease, although overall response rate was 0%. Most common treatment-related grades 3-4 adverse events were lymphopenia and leukopenia. CONCLUSION: Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify response to palbociclib + cetuximab. Additional biomarkers are needed to select anti-EGFR rechallenge and circulating tumor DNA (ctDNA) analysis is planned for samples collected in this study. (ClinicalTrials.gov Identifier: NCT03446157).

Circulating Tumor DNA in Identifying Resistant Sub-Clones Post EGFR Blockade: Implications for EGFR Rechallenge.

For patients with metastatic RAS/RAF wild-type refractory colorectal cancer, the question of anti-EGFR therapy rechallenge often comes up after initial use. However, not all patients derive benefit. It is now well known that these tumors acquire mechanisms of resistance in the mitogen-activated protein kinase (MAPK) pathway, which can be detected on circulating tumor DNA (ctDNA)-based testing. We present a series of patients who had serial testing post-EGFR blockade showing its feasibility and value. This would have implications for EGFR rechallenge. We reviewed records for patients who were initially noted to be RAS/RAF wild-type on tissue, who received prior anti-EGFR therapy and then subsequently had at least one circulating tumor DNA-based testing. These patients also had tissue-based genomic testing obtained earlier as part of their standard of care, alongside serial ctDNA-based testing that was done later when subsequent lines of therapy were being decided. The median duration of initial prior anti-EGFR therapy was around 10 months. Known acquired mechanisms of resistance were noted in 100% of the cases. These included KRAS, NRAS, extracellular domain mutations in EGFR, and BRAF mutations. Interestingly, the levels of the sub-clones expressed in variant allele fraction percentage varied and decreased over time in relation to timing of the prior EGFR exposure. Additionally, these were noted to be polyclonal, and the number of clones also varied including some disappearing over time during non-EGFR-based therapy (EGFR holiday). Patients' post-EGFR blockade may have multiple mechanisms of acquired resistance that can be easily detected on non-invasive liquid biopsies. These patients do not benefit from EGFR rechallenge based on the results of the recently reported CRICKET (NCT02296203) and CAVE (NCT04561336) clinical trials. Furthermore, excluding these patients from EGFR rechallenge is already being adopted in prospectively done clinical trials, e.g., the CHRONOS study (NCT03227926). Rechecking the liquid biopsy plasma RAS/RAF status is one thing that may be incorporated into practice with EGFR rechallenge only a consideration if acquired mechanisms of resistance are absent.

Anti-EGFR Reintroduction and Rechallenge in Metastatic Colorectal Cancer (mCRC): A Real-World Analysis.

BACKGROUND AND AIMS: In patients with Rat sarcoma proto-oncogene (RAS) wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) antibodies have been established in first- and further therapy lines. Due to limited treatment options upon disease progression, anti-EGFR re-exposure is increasingly employed in real-world oncology. The aim of this study was to assess clinical implementation and utility of anti-EGFR retreatment strategies in real-world mCRC patients. METHODS: In this monocentric retrospective study, we included 524 patients with CRC and identified patients who received an anti-EGFR-based treatment as well as anti-EGFR rechallenge (progression on first-line anti-EGFR therapy) or reintroduction (discontinuation due to intolerance/toxicity/other). RESULTS: In total, 143 patients received an anti-EGFR-based first- or second-line treatment, showing a similar overall survival (OS) compared to the non-anti-EGFR treatment group (38.3 vs. 39.6 months, p = 0.88). Thirty-three patients met the inclusion criteria for anti-EGFR re-exposure and were either assigned to rechallenge (n = 21) or reintroduction (n = 12) subgroups. The median FU after re-exposure was 45.8 months. Cetuximab and Panitumumab were used in 21 and 12 patients, respectively, and the main chemotherapy at re-exposure was FOLFIRI in 39.4%. Anti-EGFR re-exposure was associated with a distinct trend towards a better outcome (median OS 56.0 vs. 35.4 months, p = 0.06). In a subgroup comparison, reintroduction was associated with a higher OS and PFS in trend compared to the rechallenge (mOS 66 vs. 52.4, n.s., mPFS 7.33 vs. 3.68 months, n.s.). CONCLUSIONS: This retrospective study provides real-world evidence underscoring that anti-EGFR re-exposure strategies might benefit patients independently of the reason for prior discontinuation.

Remodeling of dermal adipose tissue alleviates cutaneous toxicity induced by anti-EGFR therapy.

Anti-epidermal growth factor receptor (EGFR) therapy-associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis, and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.

KRAS and NRAS mutational analysis in plasma ctDNA from patients with metastatic colorectal cancer by real-time PCR and digital PCR.

PURPOSE: Mutations in the KRAS and NRAS (RAS) genes are negative predictors of response to anti-EGFR therapy in metastatic colorectal cancer (mCRC). The detection of mutations in circulating tumor DNA (ctDNA) has emerged as a less invasive strategy to assess the molecular profile of mCRC patients. We aimed to perform RAS mutational analysis in ctDNA from mCRC patients using BEAMing Digital PCR (OncoBEAM) and Idylla ctDNA qPCR and evaluate the concordance rate with RAS mutational status in tumor tissue and between these two methodologies with different limits of detection. METHODS: Blood samples were collected from 47 mCRC patients previously tested for RAS mutations in tumor tissue. DNA was extracted from plasma using the QIAamp Circulating Nucleic Acid Kit, and RAS mutation analysis was conducted using OncoBEAM RAS CRC and Idylla ctRAS assays. RESULTS: The overall agreement between tumor tissue and ctDNA analyses was 83% and 78.7% using the OncoBEAM and Idylla assays, respectively, with the concordance being 96.2% and 88.5% in naive treatment patients. The overall agreement between OncoBEAM and Idylla ctDNA analyses was 91.7%. CONCLUSIONS: Analysis of ctDNA is a viable strategy for clinical management of mCRC patients. Although the OncoBEAM assay sensitivity is somewhat higher, the fully automated Idylla platform also has good performance, while being cheaper and much less labor-intensive, for the detection of RAS mutations in plasma, either at diagnosis or after progression when considering anti-EGFR treatment rechallenge.

Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies.

Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.

HER2 positivity as a biomarker for poor prognosis and unresponsiveness to anti-EGFR therapy in colorectal cancer.

PURPOSE: To investigate the role of HER2 positivity in prognosis and unresponsiveness to anti-EGFR therapy for colorectal cancer. METHODS: Patients who underwent primary CRC tumor resection were included. HER2 status of CRC was confirmed by immunohistochemistry and fluorescence in situ hybridization tests. Comparison of survival analysis between HER2 positivity and negativity was evaluated by a stratified log-rank test and summarized with the use of Kaplan-Meier and Cox proportional hazards methods. The treatment effects of cetuximab were further compared in full subgroup analyses. RESULT: 1240 patients were enrolled, including 763 with stage I-III CRC and 477 with stage IV CRC. 57 (4.6%) CRC patients presented HER2 positivity in the entire cohort. The survival analysis showed that patients with HER2 positivity had significantly worse disease-free survival and overall survival in stage III and IV CRC. The multivariable analysis also confirmed that HER2 positivity was a significantly independent risk factor in stage III and IV CRC. Univariate and multivariable survival analysis showed no prognostic significance of HER2 positivity in stage I-II CRC patients. Prespecified subgroup analysis showed no favorable trends in progression-free survival and overall survival for cetuximab in the patients with HER2 positivity, KRAS/NRAS/BRAF wild-type metastatic CRC (interaction P values = 0.005 and 0.014). CONCLUSION: For stage III and IV CRC patients, HER2 positivity was confirmed as an independent prognostic risk factor. It could help predict the unresponsiveness to anti-EGFR therapy for metastatic CRC.

Drug-Induced Resistance and Phenotypic Switch in Triple-Negative Breast Cancer Can Be Controlled via Resolution and Targeting of Individualized Signaling Signatures.

Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancers which is treated mainly with chemotherapy and radiotherapy. Epidermal growth factor receptor (EGFR) was considered to be frequently expressed in TNBC, and therefore was suggested as a therapeutic target. However, clinical trials of EGFR inhibitors have failed. In this study, we examine the relationship between the patient-specific TNBC network structures and possible mechanisms of resistance to anti-EGFR therapy. Using an information-theoretical analysis of 747 breast tumors from the TCGA dataset, we resolved individualized protein network structures, namely patient-specific signaling signatures (PaSSS) for each tumor. Each PaSSS was characterized by a set of 1-4 altered protein-protein subnetworks. Thirty-one percent of TNBC PaSSSs were found to harbor EGFR as a part of the network and were predicted to benefit from anti-EGFR therapy as long as it is combined with anti-estrogen receptor (ER) therapy. Using a series of single-cell experiments, followed by in vivo support, we show that drug combinations which are not tailored accurately to each PaSSS may generate evolutionary pressure in malignancies leading to an expansion of the previously undetected or untargeted subpopulations, such as ER+ populations. This corresponds to the PaSSS-based predictions suggesting to incorporate anti-ER drugs in certain anti-TNBC treatments. These findings highlight the need to tailor anti-TNBC targeted therapy to each PaSSS to prevent diverse evolutions of TNBC tumors and drug resistance development.

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subset of breast cancer with aggressive characteristics and few therapeutic options. The lack of an appropriate therapeutic target is a challenging issue in treating TNBC. Although a high level expression of epidermal growth factor receptor (EGFR) has been associated with a poor prognosis among patients with TNBC, targeted anti-EGFR therapies have demonstrated limited efficacy for TNBC treatment in both clinical and preclinical settings. However, with the advantage of a number of clinically approved EGFR inhibitors (EGFRis), combination strategies have been explored as a promising approach to overcome the intrinsic resistance of TNBC to EGFRis. In this review, we analyzed the literature on the combination of EGFRis with other molecularly targeted therapeutics or conventional chemotherapeutics to understand the current knowledge and to provide potential therapeutic options for TNBC treatment.

Health-related quality of life in patients with RAS wild-type metastatic colorectal cancer treated with panitumumab-based first-line treatment strategy: A pre-specified secondary analysis of the Valentino study.

BACKGROUND: Quality of life (QoL) patient-reported outcomes (PROs) data from pivotal first-line trials in metastatic colorectal cancer (mCRC) are poor. The Valentino study showed that de-escalation to single-agent panitumumab after 4-month induction with panitumumab-FOLFOX is inferior to panitumumab-5-FU/LV in patients with RAS wild-type mCRC, although slightly reducing toxicity. We report QoL, a secondary end-point. METHODS: PROs were assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30), EORTC QLQ-CR29, EuroQol EQ-5D questionnaires, at baseline and every 8 weeks until disease progression. First two evaluations correspond to induction treatment (identical in both arms), while subsequent to maintenance. To describe QoL changes over time, mean changes from baseline at each time point were calculated in overall population. To compare maintenance between two arms, mean changes and proportion of improved/stable/worse patients versus baseline were compared for each item. RESULTS: In arm A/B, 91.5%/92.0% of enrolled patients completed questionnaires at baseline. No significant differences in the two arms were reported in compliance, baseline scores and mean changes versus baseline for the three questionnaires during maintenance (24/32/40 weeks). Overall, mean changes versus baseline showed an early deterioration during induction with partial recovering during maintenance for global QoL, functional scales and several symptoms/items of QLQ-C30 (fatigue, nausea/vomiting, appetite loss, diarrhoea) and QLQ-CR29 (body image, dry mouth, hair loss, taste, faecal incontinence, sore skin), and EQ-5D Visual Analogue Scale (VAS) score. CONCLUSION: In patients with RAS wild-type mCRC, induction with oxaliplatin-containing chemotherapy plus anti-EGFRs induces a transient significant QoL deterioration. After induction phase, treatment deintensification determines an overall recovery of health-related QoL, besides the expected prevention of oxaliplatin-related neurotoxicity.