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.

Efficacy of a robotic stapler on symptomatic anastomotic leakage in robotic low anterior resection for rectal cancer.

PURPOSE: Clinical evidence demonstrating risk factors for anastomotic leakage including robotic staplers has remained limited, even though the use of robotic surgery has increased substantially. The purpose of this study was to evaluate the effects of robotic staplers on symptomatic anastomotic leakage in robotic low anterior resection for rectal cancer. METHODS: A total of 427 consecutive patients with primary rectal cancer who underwent robotic low anterior resection without diverting stoma were investigated retrospectively. Symptomatic anastomotic leakage was defined as anastomotic leakage of Clavien-Dindo Grade ≥ II. We compared the symptomatic anastomotic leakage rates between manual and robotic staplers using propensity score matching and investigated the risk factors for symptomatic anastomotic leakage. RESULTS: After propensity score matching, 168 pairs of manual and robotic stapler cases were selected. The symptomatic anastomotic leakage rate was significantly higher for manual staplers (6.5%) than for robotic staplers (1.2%, p = 0.02). In a multivariate analysis, the use of a manual stapler (p = 0.04, OR 4.86, 95% CI 1.08-21.8) and anastomosis < 4 cm from the anal verge (p < 0.01, OR 4.36, 95% CI 1.48-12.9) were identified as independent risk factors for symptomatic anastomotic leakage. CONCLUSIONS: Robotic stapler use was associated with a significantly decreased rate of anastomotic leakage in robotic low anterior resection without diverting stoma for rectal cancer.

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.

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.

Metastatic lymph node calcification in rectal cancer: comparison of CT and high-resolution MRI.

Calcification causes mixed signal intensity in the lymph node (LN) on high-resolution magnetic resonance imaging (MRI), which is a strong indicator of regional LN metastasis in rectal cancer. Calcified metastatic LNs in rectal cancer commonly display scattered fine punctate calcifications to varying degrees on computed tomography (CT). On high-resolution MRI, the calcifications manifest a patchy area of signal loss in corresponding calcified area that is larger than on CT. It is necessary to recognize the appearance of metastatic LN calcifications on high-resolution MRI in rectal cancer because it is the primary imaging method for local staging in rectal cancer. This pictorial essay aims to introduce an important imaging finding that can contribute to the diagnosis of LN metastasis by illustrating features and differences between CT and high-resolution MRI of metastatic LN calcifications in rectal cancer.

Rectal Metastases of Breast Carcinoma: A Case Report.

The scarcely reported hematogenous rectal metastases from breast cancer are rare and the diagnosis is challenging. They may be recognized before, concomitantly with, or after the diagnosis of the primary site of breast cancer. Invasive lobular cancer is the histological type more frequently described, and most of the affected patients have a late diagnosis. Tardive recognition is associated with poor outcomes, despite the management options. Endoscopic and imaging evaluations, mainly magnetic resonance studies, are useful, but the anatomopathological findings are mandatory to confirm the diagnostic hypothesis. We describe a middle-aged woman with advanced rectal metastases of unsuspected breast cancer found during the evaluation of manifestations due to intestinal implants. One must highlight long-term follow-up of breast cancers even if seeming in remission. The aim of this report is to enhance the suspicion index of primary health care workers.

First report of clear cell renal carcinoma metastasizing to the ischiorectal fossa 17 years after radical nephrectomy: an additional reason for lifelong follow-up.

Renal cell carcinoma has a high propensity for metastatic spread. There are several case reports of metastatic renal cell carcinomas associated with rare metastatic sites, in many cases more than ten years after the initial diagnosis. We present a 60-year-old man with perianal pain and a mass in the ischiorectal space, revealed by computed tomography. The patient had a history of clear cell renal carcinoma operated on 17 years ago. A wire localization surgical excision of the ischiorectal fossa mass was performed. The pathological report revealed a metastatic clear cell renal carcinoma. To our knowledge, this is the first case of a clear cell renal carcinoma metastasizing to the ischiorectal fossa reported in the literature. We therefore recommend that any newly discovered mass in any site of a patient with a history of renal cell carcinoma should be carefully explored and biopsied.

Significance of Lymph Node Resection After Neoadjuvant Therapy in Pancreatic, Gastric, and Rectal Cancers.

OBJECTIVE: Gastrointestinal cancers are increasingly being treated with NAT before surgical resection. Currently, quality metrics are linked to the number of LNs resected to determine subsequent treatment and prognosis. We hypothesize that NAT decreases LN metastasis, downstages patients, and decreases overall lymph node yields (LNY) compared to initial surgical resection. With increasing use of NAT, this brings into question the validity of quality metrics. METHODS: Gastric (stage II/III), pancreatic (stage I/II/III), and rectal cancers (stage II/III) (2010-2015) treated with surgery with/without NAT were identified in National Cancer Database. We evaluated total LNY and LN metastasis with/without NAT and clinical and pathological stage to evaluate rates of downstaging. RESULTS: A total of 7934 gastric, 15,908 pancreatic, and 21,354 rectal cancer patients were included of which 61.1%, 21.2%, and 85.7% received NAT, respectively. NAT patients were more likely to be downstaged (39.9% vs 11.1% gastric P< 0.001, 30.6% vs 3.2% pancreatic P< 0.001, 52.0% vs 16.3% rectal P< 0.001), have lower LNYs (18.8 vs 19.1 gastric P = 0.239, 18.4 vs 17.5 pancreatic P< 0.001, 15.7 vs 20.0 rectal P< 0.001) and have N0 pathologic disease (43.6% vs 26.7% gastric P< 0.001, 51.1% vs 30.9% pancreatic P< 0.001, 65.9% vs 49.4% rectal P< 0.001) when compared to initial surgical resection. CONCLUSION: NAT for gastrointestinal cancers results in overall lower LN yields, lower LN metastases, and significant downstaging of tumors. As all patients undergoing NAT receive multimodality therapy, LN yield recommendations may not be true quality metric changing.

A rectal metastasis of an unknown lobular breast carcinoma and its management.

Breast cancer is the most common cancer in women but gastro- intestinal metastases of breast cancer are rare. They can occur years after the diagnosis or at the diagnosis of breast cancer. We report the case of a patient complaining of dyschesia, tenesmus and anal incontinence leading to the discovery of a rectal metastasis of an unknown breast neoplasia. Given the oligo-metastatic condition, multidisciplinary and aggressive management was the chosen therapy.

[Personalized systemic treatment of metastatic colorectal cancer]. / Personalisierte Systemtherapie beim metastasierten kolorektalen Karzinom.

This article deals with the treatment of metastatic colorectal cancer (stage IV). The treatment goals and approaches are determined by the resectability status of the metastases: resectable liver and lung metastases are primarily resected and perioperative chemotherapy appears to be dispensable. In potentially resectable metastases, a conversion therapy is attempted to enable a potentially curative resection. In the case of nonresectability the treatment goal is palliative. Induction and maintenance therapy as well as drug holidays are suggested in an attempt to achieve extended survival while maintaining the quality of life, beginning with the best possible individual treatment. For some patients with stage IV, molecular targeted therapies are available. The study situation and approval status are dealt with in detail. With improved molecular characterization of tumors the treatment can be further individualized.

[Long-Term Survival of a Patient with Metastatic Ovarian Cancer and Local Recurrence of Rectal Cancer].

A 60s woman with upper rectal cancer underwent low anterior resection; the patient was diagnosed with pSSN1, Stage Ⅲa cancer. She received adjuvant therapy with UFT. Three years after the primary resection, metastasis to the right ovary and local recurrence were diagnosed. She was treated with CAPOX plus bevacizumab(Bev), capecitabine, FOLFIRI, and irinotecan plus S-1. Because only the ovarian metastasis increased rapidly, we were able to perform surgery and R0 resection. Two years after resection, local recurrence became apparent, and chemotherapy was reinitiated. After treating the patient with chemotherapy and chemo-radiation therapy for 2 years, R0 resection was performed. Twelve years after primary tumor resection and 9 years after primary resection, we observed recurrence-free survival.

Global variation in the long-term outcomes of ypT0 rectal cancers.

BACKGROUND: Colorectal cancer mortality presents world-wide variation. In rectal cancers presenting a complete/nearly-complete tumor response (ypT0/ypTis) following neoadjuvant treatment, the features correlated to nodal metastases and relapses still need to be defined. METHODS: An international cohort study enrolling ypT0/ypTis rectal cancers surgically treated from 2012 to 2017 was conducted. A propensity matching was used to balance nodal-positive and nodal-negative patients and statistical analyses were performed to investigate survivals, using a bootstrap model for internal validation. The features correlated with nodal metastasis were studied. Countries with participating centers were ranked using the World Bank (WBI), Human Development (HDI) and Global Gender Gap (GGG) indexes to compare survivals. RESULTS: 680 ypT0/ypTis from 52 European, Australian, Indian and American Institutions were analyzed. Mean follow-up was of 30.4 months. 96.5% were treated with total mesorectal excision, 7.2% were nodal-positive and 8.8% relapsed. Distal cancers (HR 0.71 95%CI: 0.56-0.91) and nodal metastasis and nodal metastasis (HR 3.85 95%CI:1.12-13.19) correlated with worse DFS, whereas a younger age was of borderline significance (HR 0.95 95%CI:0.91-0.99). The bootstrap analysis validated the model on 5000 repetitions. A short-course radiotherapy (OR 0.18 95%CI:0.09-0.37) correlated with the occurrence of nodal metastasis. Those countries classified in the low/medium-WBI, medium-HDI and lower-GGG ranks documented worse DFS curves (respectively p < 0.0001, p < 0.0001 and p 0.0002). However, the clinical stages were similar and patients from medium-HDI countries received more adjuvant chemotherapy than the others (p < 0.0001). CONCLUSION: Sub-groups at risk for relapses and nodal metastasis were identified. A global variation exists also when benchmarking a rectal cancer complete regression.