Benefit from upfront FOLFOXIRI and bevacizumab in BRAFV600E-mutated metastatic colorectal cancer patients: does primary tumour location matter?

BACKGROUND: Recent data suggest that BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients with right-sided tumours and ECOG-PS = 0 may achieve benefit from the triplet regimen differently than those with left-sided tumours and ECOG-PS > 0. METHODS: The predictive impact of primary sidedness and ECOG-PS was evaluated in a large real-life dataset of 296 BRAFV600E-mutated mCRC patients treated with upfront triplet or doublet ± bevacizumab. Biological differences between right- and left-sided BRAFV600E-mutated CRCs were further investigated in an independent cohort of 1162 samples. RESULTS: A significant interaction effect between primary sidedness and treatment intensity was reported in terms of both PFS (p = 0.010) and OS (p = 0.003), with a beneficial effect of the triplet in the right-sided group and a possible detrimental effect in the left-sided. No interaction effect was observed between ECOG-PS and chemo-backbone. In the MSS/pMMR population, a consistent trend for a side-related subgroup effect was observed when FOLFOXIRI ± bevacizumab was compared to oxaliplatin-based doublets±bevacizumab (p = 0.097 and 0.16 for PFS and OS, respectively). Among MSS/pMMR tumours, the BM1 subtype was more prevalent in the right-sided group (p = 0.0019, q = 0.0139). No significant differences were observed according to sidedness in the MSI-H/dMMR population. CONCLUSIONS: Real-life data support the use of FOLFOXIRI ± bevacizumab only in BRAFV600E-mutated mCRC patients with right-sided tumours.

Concurrent BRAFV600E and BRCA Mutations in MSS Metastatic Colorectal Cancer: Prevalence and Case Series of mCRC patients with prolonged OS.

BACKGROUND: BRAF V600E+ microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients comprise up to 10% of advanced CRC. They have a poor prognosis with a median survival typically <1 year. Despite use of multi-agent 1st line chemotherapy regimens and combination targeted therapies, outcomes are still poor. In our Institutional Molecular Tumor Board (MTB) database, we identified 3 mCRC patients with MSS/BRAF V600E who also had a BRCA1 or BRCA2 co-mutation and had relatively long overall survivals. Prior studies suggested that BRCA mutations are uncommon in CRC and we queried the Foundation Medicine (FM) genomic database to evaluate the prevalence of these cases as well as those with co-mutations in other homologous recombination genes. METHODS: 36,966 CRC pts were sequenced by FMI using hybrid capture comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) for pathogenic BRAF mutations and/or a mutation in BRCA1/2 or a co-mutation in other homologous recombination (HR) genes (BARD1, CDK12, FANCL, PALB2, ATM, RAD54L, CHEK2, BRAF, BRIP1, RAD51D, RAD51C, RAD51B, CHEK1). Selected cohort analysis of BRAF V600E co-mutated with BRCA1 and BRCA2 were separated into MSI-H and MSS cohorts. The clinicopathological features and genomic loss of heterozygosity (gLOH) of those with a BRAF V600E and a BRCA1/BRCA2 mutation were collected and analyzed. We also describe 3 consecutive cases of mCRC patients, identified through the Inova Schar Cancer Institute (ISCI) MTB registry, whom had prolonged OS. RESULTS: Of 36,966 colorectal cancer pts, 6.6% were BRAF V600E+ and 1.5% had any co-occurring HR gene mutation(s) with 0.6% of the total mCRC population having co-ocurring BRAF V600E and BRCA1/2 alterations. BRCA co-mutations were higher in MSI-High BRAF V600E, however 24.1% of co-occurrences were observed in MSS samples. BRCA1 co-mutation was more commonly associated with MSS BRAF V600E and was associated with a higher gLOH than MSI-H BRAF V600E (18.7% vs 2.8%; p <0.001). In our institutional MTB database, (3/241;1.2%) CRC patients were MSS, BRAF V600E+ with BRCA1 or BRCA2 co-mutations, all somatic in origin, with an average gLOH of 21.4% and overall survivals of 72+(alive), 17+(alive), and 30 months, respectively. CONCLUSION: Co-existence of BRAF V600E/BRCA1/2 may represent a unique subset of advanced MSS CRC that may have a better prognosis and represent an opportunity to test novel targeted therapies. The elevated gLOH in these cases may also be a valuable biomarker for these pts. Larger prospective clinical validation trials in this subset is warranted.

Gastric and colonic metastasis from NSCLC: A very unusual case report.

RATIONALE: Lung cancer is the most common cause of cancer-related deaths worldwide. Approximately 50% of patients is metastatic at diagnosis and the most common metastatic sites are bone, lungs, brain, adrenal glands, liver, and extra thoracic lymph nodes. The occurrence of gastrointestinal metastasis from lung carcinoma is rare and seems more commonly related to small cell lung cancer compared to non-small cell lung cancer (NSCLC). PATIENT INFORMATION AND DIAGNOSIS: A 78-year-old man with completely surgically resected NSCLC and no initial evidence of distant metastases developed colon and gastric metastases 7 months after diagnosis, confirmed by serial radiological examinations and endoscopic biopsies. INTERVENTIONS: The patient was subjected to total gastrectomy with D2 lymph node dissection plus partial colectomy for intraoperative detection of a transverse colon neoformation. Subsequent instrumental imaging showed bilateral lung tumor recurrence, treated with gemcitabine monotherapy for 8 months as first line chemotherapy for lung adenocarcinoma. RESULTS: The patient presented complete response to therapy and was disease-free for 4 years. LESSONS: Colonic and gastric metastasis are very infrequent in NSCLC. The resection of gastrointestinal metastasis may provide benefits in terms of both symptom control and survival in patients properly selected.

Racial differences in survival and response to therapy in patients with metastatic colorectal cancer: A secondary analysis of CALGB/SWOG 80405 (Alliance A151931).

BACKGROUND: The objective of this study was to evaluate the association between self-identified race and overall survival (OS), progression-free survival (PFS), and response to therapy among patients enrolled in the randomized Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. METHODS: Patients with advanced or metastatic colorectal cancer who were enrolled in the CALGB/SWOG 80405 trial were identified by race. On the basis of covariates (treatment arm, KRAS status, sex, age, and body mass index), each Black patient was exact matched with a White patient. The association between race and OS and PFS was examined using a marginal Cox proportional hazard model for matched pairs. The interaction between KRAS status and race was tested in the model. The association between race and response to therapy and adverse events were examined using a marginal logistic regression model. RESULTS: In total, 392 patients were matched and included in the final data set. No difference in OS (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.73-1.16), PFS (HR, 0.97; 95% CI, 0.78-1.20), or response to therapy (odds ratio [OR], 1.00; 95% CI, 0.65-1.52) was observed between Black and White patients. Patients with KRAS mutant status (HR, 1.31; 95% CI, 1.02-1.67), a performance statusscore of 1 (reference, a performance status of 0; HR, 1.49; 95% CI, 1.18-1.88), or ≥3 metastatic sites (reference, 1 metastatic site; HR, 1.67; 95% CI, 1.22-2.28) experienced worse OS. Black patients experienced lower rates and risk of grade ≥3 fatigue (6.6% vs 13.3%; OR, 0.46; 95% CI, 0.24-0.91) but were equally likely to be treated with a dose reduction (OR, 1.09; 95% CI, 0.72-1.65). CONCLUSIONS: No difference in OS, PFS, or response to therapy was observed between Black patients and White patients in an equal treatment setting of the CALGB/SWOG 80405 randomized controlled trial. LAY SUMMARY: Despite improvements in screening and treatment, studies have demonstrated worse outcomes in Black patients with colorectal cancer. The purpose of this study was to determine whether there was a difference in cancer-specific outcomes among Black and White patients receiving equivalent treatment on the CALGB/SWOG 80405 randomized clinical trial. In this study, there was no difference in overall survival, progression-free survival, or response to therapy between Black and White patients treated on a clinical trial. These findings suggest that access to care and differences in treatment may be responsible for racial disparities in colorectal cancer.

Colonic metastasis from hepatocellular carcinoma after treated by ablation and transarterial chemoembolization manifested by intestinal obstruction: A case report and review of the literature.

Hepatocellular carcinoma (HCC) with gastrointestinal tract metastasis is a rare condition. Recently, we encountered one case of HCC with direct invasion to the colon, which was manifested by intestinal obstruction. The patient was an 86-year-old man who underwent multiple transarterial chemoembolization and microwave ablation treatment for HCC lesions for 10 years. Two months after last palliative microwave ablation, computed tomography showed a 7.0-cm liver tumor directly invading the hepatic flexure of colon with the symptom of right abdominal pain and discontinuous nausea and vomiting. HCC colon metastasis with intestinal obstruction was diagnosed. Intestinal adhesion lysis and colostomy were performed. The patient survived 10 months after surgery and died of tumor progression.

Nomogram of conditional survival probability of long-term Survival for Metastatic Colorectal Cancer: A Real-World Data Retrospective Cohort Study from SEER database.

BACKGROUND: Many patients with metastatic colorectal cancer (mCRC) have better prognosis than the prediction at diagnosis. Compared with invariable traditional Kaplan Meier assessment, conditional survival (CS) assessment has become a more accurate and informative assessment method to predict survival time. MATERIALS AND METHODS: Patients with mCRC between 2010 and 2015 were extracted from Surveillance, Epidemiology and End Results linked database. CS analysis was applied to depict exact survival for patients who have survived for specific year and standardized difference (d) was used to evaluate the differences between subgroups in CS analysis. Based on variables selected by Lasso analysis, nomograms for each year after diagnosis were fitted to estimate 3-year survival of stage IV CRC, respectively. RESULTS: Of 9732 patients, overall actuarial survival (OS) decreased from 24% at 4-year to 16% at 6-year, while corresponding 3-year CS (CS3) increased from 33% at 1-year to 48% at 3-year. Overall, CS3 was higher than corresponding actuarial survival. All clinicopathological characteristics were associated with actuarial survival (p < 0.05). However, in CS3 analysis, survival difference caused by gender, race and tumor size gradually disappeared over time (|d|>0.1→ |d|<0.1). Furthermore, survival difference caused by histological type, brain metastasis and chemotherapy reversed over time (d > 0→d<0 or d<0→d>0). Based on lasso analysis, nomograms for 1st, 2nd and 3rd year after diagnosis were conducted respectively. The AUC of nomogram for 1st year was 0.705, for 2nd year was 0.675, and for 3rd year was 0.648. CONCLUSION: Patients with mCRC demonstrated a substantial increase in CS over time. Risk factors collected at diagnosis may change gradually. Nomograms constructed by survival time can predict more accurate survival for patients with mCRC. Conditional survival assessments provide important quantitative information about the probability of survival and are therefore of great value to patients and health care professionals.

Metastatic renal cell carcinoma to pancreas and gastrointestinal tract: a clinicopathological study of 3 cases and review of literature.

BACKGROUND: Renal Cell Carcinoma (RCC) metastasizes in approximately 20-30% cases. The most common sites for metastases are the lungs, bones, liver, and brain. Metastases of RCC in the gastrointestinal tract (GIT) are very rare. Metastatic RCC has a poor prognosis. We herein present a case series of three patients with metastatic disease in the colon, duodenum, and pancreas following complete resection of RCC. METHODS: Hematoxylin and Eosin and immunohistochemical slides of 3 cases of RCC metastatic to GIT were reviewed. These cases were diagnosed between 2002 and 2019 at French Medical Institute for Mothers and Children (FMIC), Kabul, Afghanistan, and Aga Khan University Hospital (AKUH), Karachi, Pakistan. We also present a detailed review of published literature. RESULTS: We reviewed cases of three patients, two females and one male, with a mean age of 57.3 years (range 40-67 years) who underwent nephrectomy for RCC. They developed metastases in the colon, pancreas, and duodenum, respectively 12-168 months (median time 156 months) following primary tumor resection. The patient with metastatic RCC in colon presented with abdominal pain and constipation. An ulcerated mass was found on colonoscopy 30 cm from the anal verge. Diagnosis of RCC with rhabdoid features was confirmed in both primary and metastatic tumors. The second patient developed a metastatic nodule in the head of pancreatic while the third patient developed metastatic nodules in the duodenum and pancreas which were detected by Computed Tomography (CT) scanning. Histopathological examination confirmed the presence of clear cell RCC in the metastatic nodules in both cases. CONCLUSION: Metastatic RCC should be considered in the differential diagnosis of mass in the gastrointestinal (including pancreaticobiliary) tract especially in presence of a past history of RCC. These patients should be screened thoroughly by physical examination and appropriate imaging studies.

Clinicopathological characteristics and survival outcomes for patients with mucinous colorectal cancer liver metastases undergoing hepatic resection: A systematic review and meta-analysis.

BACKGROUND: Mucinous adenocarcinoma represents a distinct histological subtype of colorectal cancer. To date there has been limited data available for patients with colorectal cancer liver metastases (CRCLM) derived from mucinous adenocarcinoma. This systematic review and meta-analysis aims to provide data on the clinicopathological and survival outcomes of this cohort. METHODS: Databases were searched for studies comparing clinicopathological and survival outcomes between patients with mucinous CRCLM and CRCLM from adenocarcinoma not otherwise specified who underwent liver resection. A random-effects model was used for analysis. RESULTS: Eight studies describing 9157 patients were included. Mucinous CRCLM were positively associated with colon tumors (OR 1⋅64, P = 0⋅01), T3/T4 tumors (OR 1⋅58, P = 0⋅02), node positive tumors (OR 1⋅55, P = 0⋅005). The review also identified a trend towards worse overall survival in patients with mucinous CRCLM. CONCLUSIONS: Despite the distinct clinicopathological characteristics and impaired long term outcomes of mucinous CRCLM, resection should remain the gold standard where possible.

Echinococcal hepatic lesion mimicking metastasis from colon cancer: two case reports.

BACKGROUND: Echinococcus is a worldwide zoonosis, primarily causing liver lesions. Accidentally detected, these lesions enter the differential diagnosis of a tumor, including metastasis. This situation is especially challenging in patients with colorectal cancer, as both diseases affect mainly the liver. CASE PRESENTATION: We report two patients with a newly diagnosed colorectal cancer. Pre- and intraoperatively radiological imaging revealed hepatic lesions which were resected on suspicion of colorectal cancer metastasis. Histology showed granulomatous lesions with characteristic parasitic membrane consistent with an echinococcal cyst. The diagnosis was confirmed by specific polymerase chain reaction. CONCLUSIONS: Focal hypoechoic liver lesion in patients with colorectal cancer should be primarily considered as a liver metastasis and resected whenever feasible. Other uncommon etiologies, including parasitic lesion as echinococcal cysts, should be taken in consideration, as this could lead to major changes of the management and prognosis of the affected patients.

Adenocarcinoma of the colon and urinary bladder: A fortuitous or an embryological phenomenon?

Primary adenocarcinoma of the urinary bladder is a rare malignancy with a frequency of less than 2% of all urothelial malignancies. Colonic adenocarcinoma has a much higher prevalence and its infiltration/metastasis in the urinary bladder is a pertinent differential of primary adenocarcinoma of the urinary bladder. However, the distinction of infiltration by colonic adenocarcinoma from synchronous adenocarcinoma in the bladder and colon is not always easy. Here, we report a 42-year-old male, who initially presented with bladder symptoms and subsequently found to have growth in both bladder and colon. A diagnosis of adenocarcinoma was made from the biopsies from both bladder and colon. Further attempts to differentiate synchronous occurrence or secondary involvement from an adjacent organ was made by radiology, and by an immunohistochemistry panel. The loss of MLH1 and PMS2 coupled with histomorphology and radiology helped in the diagnosis of primary colonic adenocarcinoma infiltrating the urinary bladder.

Usefulness of a Colonic Stent for Colonic Obstruction Caused by Lung Cancer Metastasis.

The gastrointestinal tract is not a common site for metastasis from lung cancer, and colonic metastases are especially rare. Although surgical intervention can improve colonic obstruction, perioperative mortality is high in patients with advanced malignancy, and these patients experience a significant deterioration in quality of life postoperatively. This report describes an uncommon case of colonic metastasis from non-small cell lung cancer (NSCLC), in which colonic obstruction was improved with a self-expanding metallic stent. A 62-year-old man was admitted to our hospital for progressively worsening abdominal pain. He had been treated with immunotherapy and chemotherapy after being diagnosed with NSCLC (T4N2M1) 1.5 years earlier. Enhanced computed tomography showed intestinal obstruction and a mass in the colon at the hepatic flexure. Histopathological analysis of a biopsy specimen confirmed NSCLC metastasis. Considering his general condition, endoscopic stenting was chosen as an urgent decompression procedure. He was discharged 45 days after stenting and was able to resume immunotherapy. Emergency stenting could be offered at experienced centers when operative intervention is not part of the treatment plan, as it is safe and improves the efficiency of care along with the quality of life.

Colon metastases as first clinical manifestation of lobular breast carcinoma with no subsequent evidence of breast disease.

A 73-year-old woman was brought to the oestrogen receptor for altered mental status. She was found to be hypotensive and hypoglycaemic and admitted to the intensive care unit. She had a history of chronic watery diarrhoea which had recently increased over the last 2 weeks and was associated with vague abdominal pain. A CT showed bowel wall thickening concerning for colitis. Due to the increasing diarrhoea, a colonoscopy was done after all stool studies came back negative. Polyps in the ascending, transverse and sigmoid colon were found to be tubular adenomas but random colonic mucosa biopsies were revealed to be histologically consistent with metastatic lobular breast carcinoma. Further workup revealed no primary breast disease.

Thoracic vertebral metastasis from progressive hepatocellular carcinoma following liver transplantation combined with resection of mesenteric and colonic metastases: A case report.

RATIONALE: Surgical treatment of spinal hepatocellular carcinoma metastasis after Liver transplantation (LT) is a clinical challenge. We herein report the clinical outcomes of the first case of a patient with T11 from hepatocellular carcinoma metastasis after systemic chemotherapy following LT combined with mesenteric resection and colectomy, who was successfully treated with En Bloc spondylectomy. PATIENT CONCERNS: The patient with HCC was a 40-year-old man, who had received LT combined with mesenteric resection and colectomy 15 months before. His main symptom was progressive back pain because of T11 metastasis. PET examinations showed a solitary metastasis at T11 without recurrence in the liver and metastasis in the other organs. DIAGNOSIS: The patient was diagnosed with the T11 vertebra HCC metastasis after LT combined with resection of HCC mesenteric metastasis and colon metastasis. INTERVENTIONS: Five cycles of systemic chemotherapy following LT were performed for preventing HCC metastases. However, the right abdominal wall metastasis was found 9 months after LT, followed by T11 metastases thereafter. Immediate resection of the right abdominal wall metastasis was achieved. En Bloc spondylectomy of T11 vertebra was chosen as a treatment for metastasis to T11. After T11 surgery, the patient showed obvious pain relief. However, At 3 months after T11 surgery, a grafted liver metastasis and multiple nodules metastasis in the greater omentum region were revealed with CT imaging, At 5 months after T11 surgery, multiple lung metastases were discovered by MRI. The patient was performed 5 cycles of chemotherapy, 3 times of infusion of iodine [131I] meximab and 3 times of TACE after T11 surgery. Multiple bone metastases were treated with radiotherapy. OUTCOMES: The patient died 29 months after LT combined with mesenteric resection and colectomy because of recurrence in the liver and metastasis in the lung. LESSONS: En Bloc spondylectomy may be a therapeutic choice for patients with progression after systemic chemotherapy for the solitary spinal metastases after LT combined with mesenteric resection and colectomy, which has a survival benefit without local recurrence at the surgical site. immunosuppressant after LT may result in worse immune function, which leads to HCC more prone to recurrence and bone metastasis.