Ready, Set, Go: Setting Off on the Mission to Target KRAS in Colorectal Cancer.

Understanding the landscape of KRAS mutations in #CRC is crucial with over 2.8M annual diagnoses worldwide. Explore promising therapies and ongoing challenges in this comprehensive review. #CancerResearch #KRAS #ColorectalCancer.

Targeting All BRAF Alterations: The (Re)-Search Continues.

VivekSubbiah & colleagues delve into the @ASCO #TAPURStudy, shedding light on the importance of targeting ALL #BRAFAlterations, beyond V600E. (Re)-search continues, urging us to push the boundaries and unlock new possibilities in #PrecisionMedicine. #CancerResearch #JCOPO.

Endoscopic and imaging outcomes of PD-1 therapy in localised dMMR colorectal cancer.

BACKGROUND: Neoadjuvant immune checkpoint blockade (IO) is emerging as a therapeutic option for patients with deficient mismatch repair (dMMR) colorectal cancer (CRC) given high pathological response rates. The aim of the study was to characterise imaging and endoscopic response to IO. METHODS: A retrospective analysis of patients with localised dMMR CRC that received at least one cycle of neoadjuvant anti-PD-1 therapy was conducted. Endoscopy, imaging, and pathological outcomes were reviewed to determine response to treatment according to standardised criteria. RESULTS: Thirty-eight patients had received IO for the treatment of localised CRC (median eight cycles). Among evaluable cases (n = 31 for endoscopy and n = 34 for imaging), the best endoscopic response was complete response (CR) in 45% of cases, and the best radiographic response was CR in 23% of cases. Imaging CR rate after ≤4 cycles of IO (n = 1) was 6% compared to 44% after >4 IO cycles (n = 7). Among 28 patients with imaging and endoscopy available, a discrepancy in best response was noted in 15 (54%) cases. At a median follow-up of 28.2 months from IO start, 18 patients underwent surgical resection of which 11 (61%) had pathological CR (pCR). Despite pCR or no evidence of progression ≥6 months after completion of IO among non-operatively managed patients, 72% and 42% of patients had non-CR on imaging and endoscopy, respectively. CONCLUSIONS: Discrepancies between imaging and endoscopy are prevalent, and irregularities identified on these modalities can be identified despite pathological remission. Improved clinical response criteria are warranted.

Tumor-agnostic drug development in dMMR/MSI-H solid tumors.

Mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) represents a distinct phenotype among solid tumors characterized by frequent frameshift mutations resulting in the generation of neoantigens that are highly immunogenic. Seminal studies identified that dMMR/MSI-H tumors are exquisitely sensitive to immune checkpoint inhibitors, which has dramatically improved outcomes for patients harboring dMMR/MSI-H tumors. Nevertheless, many patients develop resistance to single-agent immune checkpoint blockade, prompting the need for improved therapeutic options for this patient population. In this review, we highlight key studies examining the efficacy of PD1 inhibitors in the metastatic and neoadjuvant setting for patients with dMMR/MSI-H tumors, describe resistance mechanisms to immune checkpoint blockade, and discuss novel treatment approaches that are currently under investigation for dMMR/MSI-H tumors.

PARP inhibitors: enhancing efficacy through rational combinations.

Poly (ADP-ribose) polymerase inhibitors (PARPi) have significantly changed the treatment landscape for tumours harbouring defects in genes involved in homologous repair (HR) such as BRCA1 and BRCA2. Despite initial responsiveness to PARPi, tumours eventually develop resistance through a variety of mechanisms. Rational combination strategies involving PARPi have been explored and are in various stages of clinical development. PARPi combinations have the potential to enhance efficacy through synergistic activity, and also potentially sensitise innately PARPi-resistant tumours to PARPi. Initial combinations involving PARPi with chemotherapy were hindered by significant overlapping haematologic toxicity, but newer combinations with fewer toxicities and more targeted approaches are undergoing evaluation. In this review, we discuss the mechanisms of PARPi resistance and review the rationale and clinical evidence for various PARPi combinations including combinations with chemotherapy, immunotherapy, and targeted therapies. We also highlight emerging PARPi combinations with promising preclinical evidence.

Impact of tissue-agnostic approvals for patients with gastrointestinal malignancies.

Gastrointestinal (GI) malignancies encompass a broad range of tumors with limited treatment options, particularly for advanced disease. With the development and implementation of next-generation sequencing (NGS) in routine practice, molecular-targeting therapies have been increasingly incorporated into the treatment paradigm for various cancers. Several drugs have achieved tissue-agnostic regulatory approvals, which offer promising biomarker-driven therapy options for patients with advanced GI malignancies. In this review, we focus on the clinical evidence for recent drug approvals for neurotrophic tyrosine receptor kinase (NTRK) fusion, microsatellite instability-high (MSI-H) phenotype, tumor mutation burden-high (TMB-H), BRAF V600E, and rearranged during transfection (RET), in the context of GI malignancies. We also highlight the future landscape of tissue-agnostic targets, such as human epidermal growth factor receptor 2 (HER2)/neu, fibroblast growth factor receptor (FGFR), and neuregulin (NRG)-1.

An analysis of research biopsy core variability from over 5000 prospectively collected core samples.

Factors correlated with biopsy tissue adequacy and the prevalence of within-biopsy variability were evaluated. Totally, 1149 research biopsies were performed on 686 patients from which 5090 cores were assessed. Biopsy cores were reviewed for malignant percentage (estimated percentage of cells in the core that were malignant) and malignant area (estimated area occupied by malignant cells). Linear mixed models and generalized linear mixed models were used for the analysis. A total of 641 (55.8%) biopsies contained a core with <10% malignant percentage (inadequate core). The chance of an inadequate core was not influenced by core order, though the malignant area decreased with each consecutive core (p < 0.001). Younger age, bone biopsy location, appendiceal tumor pathology, and responding/stable disease prior to biopsy increased the odds of a biopsy containing zero adequate cores. Within-biopsy variability in core adequacy is prevalent and suggests the need for histological tumor quality assessment of each core in order to optimize translational analyses.

Outcomes after stereotactic radiosurgery for CNS lymphoma.

BACKGROUND: The standard of care for CNS lymphoma typically includes high dose methotrexate followed by whole brain radiation therapy, but there is an increased risk of neurotoxicity with this regimen. In our institution, we offered stereotactic radiosurgery (SRS) for disease refractory to HD-MTX in a subset of patients. A search of the literature on this modality for CNS lymphoma was also conducted. METHODS: Medical records of six patients who received partial brain radiation therapy for persistent CNS lymphoma were reviewed. SRS was given via 1-3 fractions to doses of 21 or 24 Gy. PubMed, SCOPUS, and Cochrane Library databases were systematically searched for articles reporting on outcomes for CNS lymphoma treated with SRS. RESULTS: Six patients (eleven lesions) were treated with SRS for CNS lymphomas. Median follow up was 15.6 months (range 3.3-37.8). Median RT dose per lesion was 21 Gy and median time to progression was 12.7 months. Median overall survival was not reached. Four patients had distant intracranial failure with two developing local recurrence. The search strategy yielded 16 studies of which only one was prospective and included a control group. 183 out of 256 evaluated lesions (69%) responded completely to treatment and 13 of 204 patients (6%) recurred within the treatment area at last follow-up. Overall, the treatment was well tolerated. CONCLUSION: SRS may provide favorable local control in patients with refractory CNS lymphomas. A prospective trial is warranted to validate the efficacy of such an approach.

Rapid Early Tumor Progression is Prognostic in Glioblastoma Patients.

OBJECTIVES: Determine the prognostic significance of rapid early tumor progression before radiation and chemotherapy for glioblastoma patients. METHODS: A retrospective review of glioblastoma patients was performed. Rapid early progression (REP) was defined as new enhancing tumor or >25% increase in enhancement before radiotherapy. The pre/postoperative magnetic resonance imaging was compared with the preradiation magnetic resonance imaging to determine REP. A blinded review of imaging was performed. Kaplan-Meier curves were generated to compare progression-free and overall survival (OS). Univariate analysis was performed using the log-rank test for categorical variables and Cox proportional hazards for continuous variables. Multivariable logistic regression was performed to assess factors related to early progression and Cox proportional hazards model was used for multivariate analysis of OS. RESULTS: Eighty-seven patients met entry criteria. A total of 52% of patients developed REP. The OS in the REP group was 11.5 months (95% confidence interval [CI]: 7.4-17.6) and 20.1 months (95% CI: 17.8-26.1) without REP (P=0.013). On multivariate analysis including significant prognostic factors, presence of REP was found to increase the risk of death (hazard ratio: 2.104, 95% CI: 1.235-3.583, P=0.006). A total of 74% of patients recurred in the site of REP. CONCLUSIONS: REP was common and independently predicted for a worse OS. Integrating REP with MGMT promotor methylation improved prognostic assessment. The site of REP was a common site of tumor progression. Our findings are hypothesis generating and may indicate a particular subset of glioblastoma patients who are resistant to current standard of care therapy. Further study to determine other molecular features of this group are underway.

Stereotactic radiosurgery practice patterns for brain metastases in the United States: a national survey.

BACKGROUND: Stereotactic radiosurgery (SRS) has emerged as an important modality for the treatment of intracranial metastases. There are currently few established guidelines delineating indications for SRS use and fewer still regarding plan evaluation in the treatment of multiple brain metastases. METHODS: An 18 question electronic survey was distributed to radiation oncologists at National Cancer Institute (NCI) designated cancer centers in the USA (60). Centers without radiation oncologists were excluded. Physicians who indicated that they do not prescribe SRS were excluded from the remaining survey questions. Sign test and Chi-square test were used to determine if responses differed significantly from random distribution. RESULTS: One hundred sixteen of the 697 radiation oncologists surveyed completed the questionnaire, representing 51 institutions. Sixty-two percent reported treating patients with brain metastases using SRS. Radiation oncologists prescribing SRS most commonly treat CNS (66.2%) and lung (49.3%) malignancies. SRS was used more frequently for < 10 brain metastases (73.7%; p < 0.0001) and whole brain radiation therapy (WBRT) for > 10 brain metastases (82.5%; p < 0.0001). The maximum number of lesions physicians were willing to treat with SRS without WBRT was 1-4 (40.4%) and 5-10 (42.4%) (p < 0.0001 compared to 11-15, 16-20 and no limit). The most important criteria for choosing SRS or WBRT were number of lesions (p < 0.0001) and performance status (p = 0.016). The most common margin for SRS was 0 mm (49.1%; p = 0.0021). The most common dose constraints other than critical structure was conformity index (84.2%) and brain V12 (61.4%). The LINAC was the most common treatment modality (54.4%) and mono-isocenter technique for multiple brain metastases was commonly used (43.9%; p = 0.23). Most departments do not have a policy for brain metastases treatment (64.9%; p = 0.024). CONCLUSIONS: This is one of the first national surveys assessing the use of SRS for brain metastases in clinical practice. These data highlight some clinical considerations for physicians treating brain metastases with SRS.

Bevacizumab and re-irradiation for recurrent high grade gliomas: does sequence matter?

PURPOSE/OBJECTIVES: We report the outcomes of the largest cohort to date of patients receiving both bevacizumab (BEV) and fractionated stereotactic radiotherapy (FSRT) for progressive or recurrent high grade glioma (HGG). Furthermore, the sequence of these two treatment regimens was analyzed to determine an optimal treatment paradigm for recurrent HGG. MATERIALS/METHODS: After Institutional Review Board approval, patients with pathologically confirmed WHO grade III anaplastic astrocytoma (AA) or IV glioblastoma multiforme (GBM) glioma who subsequently underwent re-irradiation at recurrence with FSRT were retrospectively reviewed. Patients from this group who had received BEV were also identified. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were analyzed as study endpoints. Date of recurrence was defined as the date of radiographic evidence of progressive/recurrent disease. Kaplan-Meier curves were generated utilizing a log-rank test with a p-value ≤ 0.05 considered significant to compare treatment sequences in terms of survival outcomes. RESULTS: A total of 118 patients with recurrent/progressive HGG (GBM = 87, AA = 31) had received both BEV and FSRT. Patient characteristics were as follows: median KPS at recurrence was 80 (range 50-100); median age at recurrence was 57 years; median time to radiographic recurrence/progression was 10.8 months (mo) and 33.1% of patients had surgery for recurrence. The median time from the start of BEV to FSRT was 6.4 months and from FSRT to the start of BEV was 5.1 months. For the entire cohort, median overall survival (OS) was 26.7 months and median survival time (MST) from recurrence was 13.8 months (24.4 months and 11.9 months for GBM only). In patients that received BEV prior to FSRT (n = 50), median OS and MST from recurrence were 25.2 and 13.3 months respectively. In patients receiving FSRT first (n = 56), median OS and MST from recurrence were 28.8 months and 13.9 months, respectively. Sequencing of BEV and FSRT at recurrence was not significantly associated with OS (p = 0.08) or median survival from recurrence (p = 0.75). CONCLUSIONS: The combination of FSRT and BEV for recurrent/progressive HGG provides promising results in terms of overall survival and survival from recurrence. Combining these treatment modalities appears to improve upon the historic outcomes of either treatment alone. The outcomes data from this study support the ongoing RTOG trial exploring the combination of BEV and FSRT for recurrent HGG.

Treatment recommendations for elderly patients with newly diagnosed glioblastoma lack worldwide consensus.

BACKGROUND: Glioblastoma predominantly occurs in the 6th and 7th decades of life. The optimal treatment paradigm for elderly patients is not well established. We sampled current worldwide management strategies for elderly patients with newly diagnosed glioblastoma. METHODS: A web-based survey was developed and distributed to 168 radiation oncologists, neuro-oncologists and neurosurgeons identified through the United Council for Neurologic Subspecialties and the CNS committees for North American, European and Asian Organizations. Questions addressed treatment recommendations in order to determine whether management consensus exists in this patient subset. RESULTS: There were 68 (40%) respondents. Across respondents, the most important factors directing treatment were KPS (94%) and MGMT methylation status (71%). Only 37% of respondents strictly factor in age when making treatment recommendations with 59% defining elderly as greater than 70 years-old. The most common treatment recommendations for MGMT-methylated elderly patients with KPS > 70 were as follows: standard chemoRT (49%), short course chemoRT (39%), and temozolomide alone (30%). The most common treatment recommendations for MGMT-unmethylated patients with KPS > 70 were as follows: short course RT alone (51%), standard chemoRT (38%), and short course chemoRT (28%). Treatment recommendations for patients with KPS < 50 were short course RT alone (40%), best supportive care (57%), or TMZ alone (17%). Individuals practicing in North America were significantly more likely to recommend standard chemoradiation for patients compared to their European counterparts. CONCLUSION: Worldwide treatment recommendations for elderly patients with newly diagnosed GBM vary widely. Further randomized studies are needed to elucidate the optimal treatment strategy for this subset of patients.

Correction to: Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment.

The fourth author's name was incorrect in the initial online publication. The original article has been corrected.

Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment.

Bevacizumab failure is a major clinical problem in the management of high grade gliomas (HGG), with a median overall survival (OS) of < 4 months. This study evaluated the feasibility and efficacy of fractionated stereotactic re-irradiation (FSRT) for patients progressed after Bevacizumab treatment. Retrospective review was conducted of 36 patients treated with FSRT after progression on bevacizumab. FSRT was most commonly delivered in 3.5 Gy fractions to a total dose of 35 Gy. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were utilized as study endpoints. Univariate and multivariate analysis was performed. The median time from initial bevacizumab treatment to FSRT was 8.5 months. The median plan target volume for FSRT was 27.5 cc. The median OS from FSRT was 4.8 months. FSRT treatment was well tolerated with no grade 3 or higher toxicity. Favorable outcomes were observed in patients with recurrent HGG who received salvage FSRT after bevacizumab failure. The treatment was well tolerated. Prospective study is warranted to further evaluate the efficacy of salvage FSRT for selected patients with recurrent HGG amenable to FSRT, who had failed bevacizumab treatment.

Re-irradiation for recurrent glioblastoma multiforme.

As our understanding of normal brain tissue tolerance and radiation technology have improved, central nervous system (CNS) re-irradiation has garnered more attention; whereas, in the past there had been hesitancy due to late toxicity concerns, particularly radionecrosis (RN). There is minimal prospective data evaluating repeat radiation in recurrent gliomas. In this review, the rationale for and different approaches to re-irradiation will be discussed, and the biology and clinical impact of late CNS toxicity will be reviewed.