Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

Binimetinib, encorafenib and cetuximab (BEACON Trial) combination therapy for patients with BRAF V600E-mutant metastatic colorectal cancer.

BRAF V600E mutations are associated with 8-10% of metastatic colorectal cancers (mCRC) and carry a poor prognosis with limited therapeutic options. In contrast to metastatic melanoma, BRAF inhibition alone or in combination with mitogen-activated protein kinase kinase (MEK) inhibitors has shown little utility in the treatment of BRAF V600E-mutant mCRC. This is secondary to upstream activation of the epidermal growth factor receptor (EGFR) pathway and other escape mechanisms. Combining RAF and MEK inhibitors with inhibition of the EGFR pathway through an anti-EGFR receptor antibody (cetuximab) led to the BEACON clinical trial (binimetinib, encorafenib and cetuximab). Trial patients had undergone at least one prior line of chemotherapy. The trial met all its endpoints and is now included in NCCN (National Comprehensive Cancer Network) guidelines. Herein we provide updates in treatment options for patients with BRAF V600E-mutant mCRC, focusing on the practice-changing BEACON-triplet regimen, the first chemotherapy-free combination regimen for mCRC. This combination is being explored frontline in the ANCHOR clinical trial.

Telotristat ethyl for the treatment of carcinoid syndrome diarrhea not controlled by somatostatin analogues.

Telotristat ethyl (Xermelo), developed by Lexicon Pharmaceuticals, is an oral tryptophan hydroxylase inhibitor blocking peripheral conversion of tryptophan to serotonin (5-hydroxytryptamine [5-HT]). It was approved by the U.S. Food and Drug Administration (FDA) in February 2017 and by the European Commission in September 2017 for patients with carcinoid syndrome in whom diarrhea is not adequately controlled by somatostatin analogues (SSAs). Diarrhea, secondary to the release of serotonin, is the predominant gastrointestinal symptom in patients with carcinoid syndrome and has a significant impact on patients' quality of life. Telotristat is not meant for all patients with diarrhea and carcinoid syndrome. Prescribing of telotristat for patients with diarrhea refractory to SSAs requires careful consideration and an approach that involves identifying and ruling out other common causes of diarrhea in patients with carcinoid syndrome. Delineating the timing of diarrhea and whether it occurs in patients with stable disease versus cancer progression can help identify the right drug candidates for therapy.

Determining the risk factors and prevalence of osteoporosis using quantitative ultrasonography in Pakistani adult women.

INTRODUCTION: Osteoporosis-related bone fractures are a significant public health problem. The aim of this study was to determine the prevalence of osteoporosis among Pakistani women and identify modifiable risk factors. METHODS: A cross-sectional study was conducted in an obstetrics / gynaecology setting during March-April 2007 in Quetta, Pakistan. A total of 334 women older than 20 years of age underwent quantitative ultrasonography and were interviewed to find out the risk factors for osteoporosis. Bone mineral density was assessed by the speed of sound using a quantitative ultrasound device. The sociodemographic characteristics of normal, osteopenic and osteoporotic women were compared using the chi-square test for categorical variables and ANOVA for continuous variables. Binary logistic regression was used to determine the independent predictors of being osteopenic or osteoporotic. RESULTS: 146 (43.7 percent) women were reported to be normal, 145 (43.4 percent) were osteopenic and 43 (12.9 percent) were osteoporotic. The mean age and standard deviation of the participants were 36.7 years +/- 13.0 years, with a body mass index (BMI) of 25.81 (standard deviation 5.10) kg per square metre. In the univariate analysis, factors that were associated with osteoporosis / osteopenia included age, parity, BMI, smoking (pack years), consumption of calcium-rich food/week, personal and family history of osteoporosis, education and socioeconomic status (p-value is less than 0.05). Using binary logistic regression with osteoporosis / osteopenia as an outcome compared to normal individuals, BMI, smoking pack years, a family history of osteoporosis / fracture and house ownership were found to be independent predictors of the outcome. CONCLUSION: The prevalence of osteoporosis and osteopenia is high, especially among young Pakistani women, and is associated with modifiable risk factors.