Metastatic Colorectal Carcinoma Research Articles

Radioembolization in the Setting of Systemic Therapies.

90 Yttrium (Y90) radioembolization has been shown to improve outcomes for primary and metastatic liver cancers, but there is limited understanding of the optimal timing and safety of combining systemic therapies with Y90 treatment. Both therapeutic effects and toxicities could be synergistic depending on the timing and dosing of different coadministration paradigms. In particular, patients with liver-only or liver-dominant metastatic disease progression are often on systemic therapy when referred to interventional radiology for consideration of Y90 treatment. Interventional radiologists are frequently asked to offer insight into whether or not to hold systemic therapy, and for how long, prior to and following transarterial therapy. This study reviews the current evidence regarding the timing and safety of systemic therapy with Y90 treatment for hepatocellular carcinoma, metastatic colorectal carcinoma, intrahepatic cholangiocarcinoma, metastatic neuroendocrine tumors, and other hepatic metastases. A particular focus is placed on the timing, dosing, and toxicities of combined therapy.

Neoadjuvant chemotherapy for colorectal liver metastases: A contemporary review of the literature.

Colorectal carcinoma (CRC) is one of the leading causes of cancer-related deaths worldwide, and up to 50% of patients with CRC develop colorectal liver metastases (CRLM). For these patients, surgical resection remains the only opportunity for cure and long-term survival. Over the past few decades, outcomes of patients with metastatic CRC have improved significantly due to advances in systemic therapy, as well as improvements in operative technique and perioperative care. Chemotherapy in the modern era of oxaliplatin- and irinotecan-containing regimens has been augmented by the introduction of targeted biologics and immunotherapeutic agents. The increasing efficacy of contemporary systemic therapies has led to an expansion in the proportion of patients eligible for curative-intent surgery. Consequently, the use of neoadjuvant strategies is becoming progressively more established. For patients with CRLM, the primary advantage of neoadjuvant chemotherapy (NCT) is the potential to down-stage metastatic disease in order to facilitate hepatic resection. On the other hand, the routine use of NCT for patients with resectable metastases remains controversial, especially given the potential risk of inducing chemotherapy-associated liver injury prior to hepatectomy. Current guidelines recommend upfront surgery in patients with initially resectable disease and low operative risk, reserving NCT for patients with borderline resectable or unresectable disease and high operative risk. Patients undergoing NCT require close monitoring for tumor response and conversion of CRLM to resectability. In light of the growing number of treatment options available to patients with metastatic CRC, it is generally agreed that these patients are best served at tertiary centers with an expert multidisciplinary team.

Single-cell exome sequencing reveals multiple subclones in metastatic colorectal carcinoma

BackgroundColorectal cancer (CRC) is a major cancer type whose mechanism of metastasis remains elusive.MethodsIn this study, we characterised the evolutionary pattern of metastatic CRC (mCRC) by analysing bulk and single-cell exome sequencing data of primary and metastatic tumours from 7 CRC patients with liver metastases. Here, 7 CRC patients were analysed by bulk whole-exome sequencing (WES); 4 of these were also analysed using single-cell sequencing.ResultsDespite low genomic divergence between paired primary and metastatic cancers in the bulk data, single-cell WES (scWES) data revealed rare mutations and defined two separate cell populations, indicative of the diverse evolutionary trajectories between primary and metastatic tumour cells. We further identified 24 metastatic cell-specific-mutated genes and validated their functions in cell migration capacity.ConclusionsIn summary, scWES revealed rare mutations that failed to be detected by bulk WES. These rare mutations better define the distinct genomic profiles of primary and metastatic tumour cell clones.

448P Efficacy of combinations of BRAF inhibitors and anti-EGFR antibodies in metastatic colorectal carcinoma (mCRC) patients with mBRAF in the real clinical practice

Combination of BRAF inhibitors and anti-EGFR antibodies is a standard of 2nd and subsequent line of treatment in pts with mBRAF mCRC. We performed analysis of prospective multicentric database of pts with mBRAF metastatic CRC to evaluate the efficacy of such approach in the real clinical practice.

419P XELOX/XELIRI alternative regimen as first-line treatment of metastatic colorectal cancer (CCRCTO-2: TROT): A phase II study

Since 2000, the combination of three drugs and targeted drugs has further improved the survival of metastatic colorectal carcinoma(mCRC), while the incidence of side effects of triple regimens over grade 3 are much higher than double regimens. Since adjusting the dosage of drugs can’t avoid serious toxicity, here we present a new methode of optimizing the scheme by adjusting the time and mode of administration.

TPC2 targeting evolution: Leveraging therapeutic opportunities for cancer

Growing evidence implicates a vital role for TPC2/Ca2+ signaling in pathophysiological processes attributed to cancer, raising questions regarding the utility of TPC2 as a cancer therapeutic target. In this issue of Cell Chemical Biology, Müller etal. (2021) develop TPC2 inhibitors, SG005 and SG-094, exhibiting anti-tumor effects with potential translational relevance.

BRAF testing in metastatic colorectal carcinoma and novel, chemotherapy-free therapeutic options.

In the past 25 years, treatment of metastatic colorectal cancer (mCRC) has undergone profound changes. The approval of newer chemotherapeutics such as irinotecan and oxaliplatin was followed in 2005 by the first targeted therapies, for example, monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), as cetuximab and panitumumab, or the angiogenesis inhibitors bevacizumab, ramucirumab, and aflibercept. With the rapidly progressing molecular characterization of mCRC in the last 10 years and the classification of the disease in four consensus subtypes, further changes are emerging, which will promote, among other things, the introduction of protein-kinase inhibitors developed for specific molecular aberrations as well as immune checkpoint inhibitors into the treatment algorithm.Thorough molecular pathologic testing is indispensable today for guideline-compliant treatment of mCRC patients. In addition to RAS testing as a precondition for the therapy decision with regard to cetuximab and panitumumab, BRAF testing is of considerable relevance to allow decision making with regard to the newly approved chemotherapy-free combination of the BRAF inhibitor encorafenib and cetuximab in cases where a BRAF-V600E mutation is detected. Additional diagnostic tests should also include genome instability (microsatellite instability). Overall, more and more molecular alterations need to be investigated simultaneously, so that the use of focused next-generation sequencing is increasingly recommended.This overview describes the prognostic relevance of BRAF testing in the context of molecular pathologic diagnostics of mCRC, presents new treatment options for BRAF-mutated mCRC patients, and explains which modern DNA analytical and immunohistochemical methods are available to detect BRAF mutations in mCRC patients.

P43-9 A 10-year marathon, race against time: Challenges in management of metastatic colon cancer

This poster illustrates the management of initially locally advanced colon carcinoma and followed by metastatic disease over a course of 10 years. It reflects our challenges in managing not only the cancer itself but also the toxicities related to treatment. In the last 10 to 15 years there are major advancements in treatment of metastatic colorectal carcinoma. With 5-Fluorouracil (5-FU) alone, the median survival has been reported as 11 to 12 months. However with more new agents other than 5-FU, for example other new cytotoxic agents, biologic agents targeting angiogenesis and the epidermal growth factor receptor (EGFR), the average median survival is approaching 3 years (Heinemann et al). Past and current treatment history was obtained retrospectively through electronic medical records. Madam L was first diagnosed with Dukes C Transverse Colon Carcinoma pT3N2M0 in 2010. However she developed metastatic disease subsequently in 2011. She failed a total 11 lines of chemotherapy and targeted therapy, including XELOX, XELIRI, FOLFIRI, TS-1, Regarofenib used with combination of Cetuximab, Panitumumab, Aflibercept. She suffered from side effects of both chemotherapy and targeted therapy, which some has been managed medically and some disabling enough to lead to cessation of the agent. She was given multiple chemo-holidays in between treatments. Over the course of 10 years, with advancement in treatment and new laboratory investigations for mutation, this patient has been on newer treatments. She is still undergoing palliative chemotherapy and is asymptomatic now. This patient has beaten the odds, by proper sequencing of chemotherapy and targeted therapy, besides adequate management of treatment related toxicity.

Management of Metastatic Colorectal Carcinoma in Older Adults: Balancing Risks and Benefits of Novel Therapies.

The prevalence of older patients with metastatic colorectal cancer (mCRC) will continue to increase with our aging population. Treatment of mCRC has changed significantly in the last few decades as we have learned how to personalize the treatment of mCRC to the biology of the tumor, utilizing new treatment approaches. With an ever-changing treatment paradigm, managing the population of older adults becomes paramount. This review highlights the pivotal clinical trials that defined the use of systemic therapy, immunotherapy and targeted therapies for mCRC, and how those are applied to the older patient population. In addition, we outline the tools for an in-depth assessment of an older adult in regards to treatment planning and management of therapy-related toxicities. A comprehensive geriatric assessment can assist in the selection of treatment for an older adult with mCRC. While frail older patients can frequently only tolerate single agents or modified regimens, fit older adults remain candidates for a wider range of treatment options. However, since all of these treatments are associated with possible toxicities, each patient's treatment must be personalized to the patient's goals and wishes through a shared decision-making process.

Metastatic Liver Tumors in Surgical Pathology: Impact of Contemporary Diagnostic and Therapeutic Paradigms in a Tertiary Care Center.

We analyzed metastatic liver tumors received in the department of pathology in a tertiary care center over a 3-year period. There were 509 metastatic liver tumors; counterintuitively, there were as many resections (235 cases) as biopsies (274 cases). This unexpected finding reflects contemporaneous organ-specific paradigms for diagnosis and management of metastatic liver disease in oncologic practice, and the association of our practice with a National Cancer Institute-designated comprehensive cancer center with expertise and specialization in liver surgery. We receive a large number of resections for metastatic liver tumors because metastasectomy from a variety of primary tumors is associated with improved overall, and in many instances, disease-free, long-term survival. Metastatic colorectal carcinomas, metastatic neuroendocrine tumors, and metastatic gastrointestinal stromal tumors constituted 78% of resections because the largest body of literature and cumulative experience exists for these lesions. In contrast, breast carcinomas and pancreatic carcinomas, which are the next common metastatic liver tumors were biopsied but rarely resected, because metastasectomy is not the standard of care for these tumors. Immunohistochemistry was performed in less than a quarter of the total number of cases (23%), because the primary tumor site was known in the vast majority of cases. Of the 42 cases with unknown primary tumor, it was elucidated in 50% of the cases by immunohistochemical and clinical work-up. Of the cases with known primary tumor, immunohistochemistry was performed mostly in metastatic breast, colon, and lung carcinomas. In these cases, biomarker analyses provided additional information relevant to clinical management.

Artificial Intelligence Can Cut Costs While Maintaining Accuracy in Colorectal Cancer Genotyping.

Rising cancer care costs impose financial burdens on health systems. Applying artificial intelligence to diagnostic algorithms may reduce testing costs and avoid wasteful therapy-related expenditures. To evaluate the financial and clinical impact of incorporating artificial intelligence-based determination of mismatch repair/microsatellite instability status into the first-line metastatic colorectal carcinoma setting, we developed a deterministic model to compare eight testing strategies: A) next-generation sequencing alone, B) high-sensitivity polymerase chain reaction or immunohistochemistry panel alone, C) high-specificity panel alone, D) high-specificity artificial intelligence alone, E) high-sensitivity artificial intelligence followed by next generation sequencing, F) high-specificity artificial intelligence followed by next-generation sequencing, G) high-sensitivity artificial intelligence and high-sensitivity panel, and H) high-sensitivity artificial intelligence and high-specificity panel. We used a hypothetical, nationally representative, population-based sample of individuals receiving first-line treatment for de novo metastatic colorectal cancer (N = 32,549) in the United States. Model inputs were derived from secondary research (peer-reviewed literature and Medicare data). We estimated the population-level diagnostic costs and clinical implications for each testing strategy. The testing strategy that resulted in the greatest project cost savings (including testing and first-line drug cost) compared to next-generation sequencing alone in newly-diagnosed metastatic colorectal cancer was using high-sensitivity artificial intelligence followed by confirmatory high-specificity polymerase chain reaction or immunohistochemistry panel for patients testing negative by artificial intelligence ($400 million, 12.9%). The high-specificity artificial intelligence-only strategy resulted in the most favorable clinical impact, with 97% diagnostic accuracy in guiding genotype-directed treatment and average time to treatment initiation of less than one day. Artificial intelligence has the potential to reduce both time to treatment initiation and costs in the metastatic colorectal cancer setting without meaningfully sacrificing diagnostic accuracy. We expect the artificial intelligence value proposition to improve in coming years, with increasing diagnostic accuracy and decreasing costs of processing power. To extract maximal value from the technology, health systems should evaluate integrating diagnostic histopathologic artificial intelligence into institutional protocols, perhaps in place of other genotyping methodologies.

Metastatic colorectal carcinoma to the right atrium: a case report and review of the literature

BackgroundCardiac metastasis due to colon cancer is extraordinarily uncommon. Given the rarity of diagnosis, there is paucity of evidence and hence, no established guidelines for evaluation or clinical management strategy.Clinical presentationWe present the case of a 59 year old male with a previously treated colonic carcinoma who presented with new onset exertional dyspnea. He was noted to be having a right atrial mass on an echocardiogram performed at his cardiologist’s office. Further workup with CT angiogram of the chest confirmed a right atrial mass measuring 4.0 cm. Serum CEA was normal. Biopsies of the right atrial mass demonstrated metastatic moderately differentiated colonic adenocarcinoma. Mismatch repair protein expression analysis by immunohistochemistry showed no loss of MLH1, MSH2, MSH6 or PMS2 expression. Next generation sequencing for RAS and BRAF mutations was negative. Patient received treatment with FOLFIRINOX/ bevacizumab with noted reduction in size of mass.ConclusionTo the best of our knowledge, this is the first report of next generation sequencing results available on a biopsy of metastatic colorectal cancer to the heart with the largest literature review of 31 reported cases of metastatic colorectal cancer to the heart. It will help direct clinical management and also adds evidence to the potential efficacy of treatment of this rare aggressive disease with chemotherapy in combination with VEGF inhibitors.

A multiple network-based bioinformatics pipeline for the study of molecular mechanisms in oncological diseases for personalized medicine.

MotivationAssessment of genetic mutations is an essential element in the modern era of personalized cancer treatment. Our strategy is focused on ‘multiple network analysis’ in which we try to improve cancer diagnostics by using biological networks. Genetic alterations in some important hubs or in driver genes such as BRAF and TP53 play a critical role in regulating many important molecular processes. Most of the studies are focused on the analysis of the effects of single mutations, while tumors often carry mutations of multiple driver genes. The aim of this work is to define an innovative bioinformatics pipeline focused on the design and analysis of networks (such as biomedical and molecular networks), in order to: (1) improve the disease diagnosis; (2) identify the patients that could better respond to a given drug treatment; and (3) predict what are the primary and secondary effects of gene mutations involved in human diseases.ResultsBy using our pipeline based on a multiple network approach, it has been possible to demonstrate and validate what are the joint effects and changes of the molecular profile that occur in patients with metastatic colorectal carcinoma (mCRC) carrying mutations in multiple genes. In this way, we can identify the most suitable drugs for the therapy for the individual patient. This information is useful to improve precision medicine in cancer patients. As an application of our pipeline, the clinically significant case studies of a cohort of mCRC patients with the BRAF V600E-TP53 I195N missense combined mutation were considered.AvailabilityThe procedures used in this paper are part of the Cytoscape Core, available at (www.cytoscape.org). Data used here on mCRC patients have been published in [55].Supplementary InformationA supplementary file containing a more detailed discussion of this case study and other cases is available at the journal site as Supplementary Data.

Expanding indications for liver transplantation in the era of liver transplant oncology.

Despite numerous advances and emerging data, liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications. In an era of persistent organ shortage and increasing organ demand, allocation of liver grafts must be considered carefully. While hepatocellular carcinoma and hilar cholangiocarcinoma have become accepted indications for transplantation, tumor size and standardized multi-disciplinary treatment protocols are necessary to ensure optimal patient outcomes. As more studies seeking to expand the oncologic indications for liver transplantation are emerging, it is becoming increasingly clear that tumor biology and response to therapy are key factors for optimal oncologic outcomes. In addition, time from diagnosis to transplantation appears to correlate with survival, as stable disease over time portends better outcomes post-operatively. Identifying aggressive disease pre-transplant remains difficult with current imaging and tissue sampling techniques. While tumor size and stage are important prognostic predictors for most malignancies, patient and tumor selection protocols are necessary. As the fields of medical and surgical oncology continue to evolve, it is clear that a protocolized interdisciplinary treatment approach is necessary for combatting any cancer effectively. Disease stability over time and response to neoadjuvant therapy may be the best predictors for successful patient outcomes and can be easily incorporated in our treatment paradigms. Current data evaluating liver transplantation for expanded oncologic indications such as: expanded criteria hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed tumors, and liver limited metastatic colorectal carcinomas, incorporate multi-modal therapies and evaluation of tumor treatment response. While further investigation is necessary, initial results suggest there is an expanded role for transplant surgery in malignancy in a new era of liver transplant oncology.

KRAS, NRAS and BRAF mutational status and first line treatment patterns in Slovenian population with metastatic colorectal carcinoma: Five year results.

e15546 Background: A phase IV non-interventional study was performed from 2013 till 2018 including 650 patients with primary aim to assess KRAS, NRAS and BRAF mutational status in Slovenian population with metastatic colorectal carcinoma (mCRC) suitable for first-line treatment. The evaluation of decisions for first-line treatment regarding the biomarkers status and assessing the possible impact of the time period of the biomarker status analysis report on the treatment decision were also incorporated in the analysis. The molecular analyses for KRAS and NRAS gene mutations were performed on exons 2, 3 and 4, and for BRAF gene mutations on exon 15. The first line systemic treatment options for RAS (KRAS/NRAS) wild type (wt) and mutated type (mt) mCRC subjects were as follows: chemotherapy - Fluoropyrimidine based systemic therapy combined with oxaliplatin and/or irinotecan with/without VEGF inhibitor bevacizumab and for RAS wt subjects, with/without EGFR inhibitors, cetuximab or panitumumab. Methods: To indicate the degree of certainty of KRAS, NRAS and BRAF status frequency as being wild type or mutant type 95% confidence interval was calculated. Results: The KRAS/NRAS/BRAF mutation rates were as follows - The distribution of subjects with KRAS mutated and wild-type tumors, was almost equal, 48.8% and 47.9% respectively. Eighty nine percent of the subjects had NRAS wild type tumours and 86.1% had BRAF wild type tumours. The most frequently used treatment regardless the biomarkers status and in accordance with the treatment guidelines was bevacizumab based combination therapy (53.1%). The EGFR inhibitor (cetuximab or panitumumab) based combination therapy was used in one third of mCRC subjects (30.9%), all with mCRC RAS wt. The time period from the initial presentation of the patient until the biomarker status analysis report was two weeks. Conclusions: With this study, we have proven that the distribution of the mutations in exons 2-4 of KRAS and NRAS genes and exon 15 in the BRAF gene in the Slovenian population with metastatic colorectal cancer matches historical data. Based on this, we conclude that the treatment decision in Slovenian population with metastatic colorectal carcinoma should be in the accordance with international treatment guidelines and on evidence based medicine. The molecular analysis performed at the Institute of Oncology Ljubljana was providing necessary biomarkers status report in an acceptable time that didn’t affect the treatment decision or delay the needed cancer treatment.

DNA mismatch repair and microsatellite instability in colorectal tumors: An observational study in the Veterans Affairs Health Care System.

e15562 Background: Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) cancers exhibit high mutational load and are observed in colorectal carcinomas (CRC). The objectives of this study were to determine the proportion of MSI-H/dMMR in CRC and to describe clinical and demographic characteristics among MSI-H/dMMR and non-MSI-H/dMMR CRC patients receiving standard of care in an equal access health care system. Methods: Using the Veteran Affairs (VA) Healthcare system data, we conducted a retrospective study of patients, aged ≥18 years old, diagnosed with CRC who underwent MSI/MMR testing from January 1, 2010 to December 31, 2018. MSI/MMR testing was defined as having received an MSI status determined by polymerase chain reaction and/or next-generation sequencing test or an MMR status determined by immunohistochemistry test. Median and interquartile range (IQR) were calculated for continuous variables while frequencies and percentages were calculated for categorical variables. Results: A total of 291 patients diagnosed with CRC who underwent MSI/MMR testing between 2010-2018 were identified from VA centers. The majority of patients were white (69.8%) and male (95.5%), with median (IQR) age of 65 (56-70) years at diagnosis. Sixty-four (22.0%) patients had stage I CRC at diagnosis, 84 (28.9%) stage II, 87 (29.9%) stage III, and 45 (15.5%) stage IV; 11 (3.7%) had no stage information. Fifty-four (18.6%) patients were reported to have MSI-H and/or dMMR CRC, with rates similar for MSI-H [17.4% (21/121)] vs. dMMR [19.7% (44/223)] alone. The proportion of MSI-H/dMMR varied by CRC stage, and was more common in stage II (26%) and stage III (23%) than in stage IV (6%). Patients were similar between MSI-H/dMMR and non-MSI-H/dMMR with regards to age at diagnosis, gender, race, and ethnicity. Of 54 patients with MSI-H/dMMR CRC, three had metastatic CRC (mCRC) at diagnosis and seven progressed to mCRC. Among 51 MSI-H/dMMR patients without metastatic disease at diagnosis, 18 (35%) underwent chemotherapy and 44 (86%) underwent curative surgery. A similar pattern was also observed among non-MSI-H/dMMR CRC patients. Conclusions: In this real-world observational study in a VA population, we found MSI-H/dMMR was present in 18.6% of CRC patients who received MSI testing, highest in stage II (26%) and stage III (23%) and lowest in stage IV (6%) disease. Results are consistent with published estimates seen across other populations and geographies. Additional research is needed in larger cohorts of patients to further assess utilization patterns and real-world clinical outcomes of newer treatments (immunotherapies) approved for MSI-H/dMMR CRC.

Metastasectomy in colorectal carcinoma (CRC) patients (pts) with mBRAF: Prospective database analysis.

e15549 Background: Role of metastasectomy in pts with mBRAF metastatic CRC is still controversial. We performed analysis of prospective multicentric database of pts with mBRAF mCRC to evaluate the efficacy of metastasectomy in such group of pts in the real clinical practice. Methods: We analyzed a database of pts with mCRC in 7 cancer clinics in Russia and chose pts with metastasectomy with different mutational status. The primary endpoints were disease free survival (DFS) and overall survival (OS), which were calculated from the time of metastasectomy. Analysis was performed with the SPSS v.20 software package. Results: The study included 126 pts: 26 pts with mBRAF, 57 pts with mRAS and 43 pts with wtRAS/BRAF. Pts with mBRAF more often had synchronous metastases (50%/19,3/11,6%, p<0,01), N2 status (38,5%/11%/19,6%, p=0,04). In mBRAF cohort all but 1 pt had V600 mutations; peritonectomy performed in 19,2%, liver resection – in 34,6%, lung resection, ovariectomy, metastasectomy in brain and retroperitoneal lymph nodes dissection with removal of the local relapse – over 11,5%; R0 resection was achieved in 88,5%. Median DFS was 7 months in mBRAF pts, 14 months in mRAS and not achieved in wtRAS/BRAF group treated (HR 2,1, 95%CI 1,5-3.1, p<0.01). Median OS was 26 months in mBRAF, 38 months in mRAS and not achieved in wtRAS/BRAF group (HR 1,5, 95%CI 1,0-2,4, p=0.06). Perioperative chemotherapy didn’t improve DFS in pts with mBRAF (HR 1,9, 95%CI 0,67-5,7, p=0,2). The best median DFS were in pts after ovariectomy – 10 months, the worst - after retroperitoneal lymph nodes dissection with removal of the local relapse – 2 months. Conclusions: Prognosis of pts with mBRAF after metastasectomy is worse than with other mutational phenotypes. However in selected cases metastasectomy might be considered in such aggressive mCRC.

FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma.

The FDA approved pembrolizumab on June 29, 2020, for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer with no prior systemic treatment for advanced disease. The approval was based on data from Study Keynote-177, which randomly allocated patients to receive either pembrolizumab or standard of care (SOC) with chemotherapy. Overall survival (OS) and independently assessed progression-free survival (PFS) were the primary endpoints. At the time of the final PFS analysis and second prespecified interim OS analysis, the estimated median PFS was 16.5 months (95% CI: 5.4-32.4) versus 8.2 months (95% CI: 6.1-10.2) in the pembrolizumab and SOC arms, respectively [HR: 0.60 (95% CI: 0.45-0.80); two-sided P = 0.0004]. FDA assessed unblinded OS data during the review of the application and identified no safety concerns that would preclude approval of this supplement. Adverse reactions occurring in >30% of patients receiving pembrolizumab were diarrhea, fatigue/asthenia, and nausea. Adverse reactions occurring in >30% of patients receiving SOC were diarrhea, nausea, fatigue/asthenia, neutropenia, decreased appetite, peripheral neuropathy (high-level term), vomiting, abdominal pain, constipation, and stomatitis. Duration of treatment in the pembrolizumab arm was almost double (median 11.1 months, range 0-30.6 months) than the duration of treatment in patients receiving SOC (median, 5.7 months). Approval of pembrolizumab is likely to change the treatment paradigm for first-line treatment with MSI-H advanced colorectal cancer given the study results and different safety profile.

Multi-gene custom panels for the characterisation of metastatic colorectal carcinoma in clinical practice: express the role of PIK3CA mutations

AimsIn metastatic colorectal carcinomas (mCRC), RAS/RAF genes mutations are first tested to determine the eligibility for anti-EGFR (Epidermal Growth Factor Receptor) therapy in combination with conventional cytotoxic agents. Recent advancements...

Obstructive Sleep Apnea Worsens Progression-Free and Overall Survival in Human Metastatic Colorectal Carcinoma.

Sleep disorders have emerged as highly prevalent conditions, and along with improved understanding of such disorders, increased attention has gained the evidence that perturbation in sleep architecture and continuity may initiate, exacerbate, or modulate the phenotypic expression of multiple diseases including cancer. Furthermore, obstructive sleep apnea (OSA) has recently been implicated in increased incidence and more adverse prognosis of cancer in humans. This study was designed to confirm the high prevalence of OSA in human malignancies and assess its prognostic relevance in metastatic colorectal carcinomas (mCRCs). A prospective cohort of 52 subjects, affected by solid histologically confirmed metastatic malignancies, was analyzed, and among them, 29 mCRCs were studied for the prognostic role of OSA. OSA was diagnosed in 34.6% (18/52) of patients with a statistically significant difference in apnea-hyponea index between OSA and non-OSA subgroups (14.2 ± 12.2 vs. 2.1 ± 1.5, p < 0.01). Consistently, OSA was diagnosed in 34.5% (10/29) of mCRCs with lower rates of first-line therapy disease control in OSA compared to non-OSA patients (60% in OSA vs. 94.7% in non-OSA, p=0.03). Of note, progression-free and overall survival rates were significantly shorter in OSA (respectively, 9 and 22 months) compared non-OSA (20 and 40 months) mCRC patients (HR = 2.63; 95% CI 0.88–7.84, p=0.01 for PFS; HR = 3.93; 95% CI 1.13–13.73, p < 0.001 for OS). Finally, the multivariate analysis showed that OSA is an independent prognostic factor for PFS (p=0.0076) and OS (p=0.0017) in this cohort. Altogether, these data suggest that OSA is a potential clinical marker predictor of poor prognosis in patients with mCRC.