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Guidelines for genetic risk assessment for cancer

Patients with a personal or family history of cancer may carry a germline genetic alteration in one of the BRCA genes or in another gene that increases the risk for cancer, and some such patients are appropriate candidates for genetics counseling and testing. Based on a systematic review, the United States Preventive Services Task Force (USPSTF) has recommended that women with a personal or family history of breast or ovarian cancer be evaluated with a familial risk assessment tool to determine whether they should proceed with genetics counseling [1,2]. However, in the setting of differing guidelines from expert groups, we continue to use the National Comprehensive Cancer Network (NCCN) criteria to select candidates for genetics evaluation, in part because risk assessment tools are cumbersome to use in a clinical setting and there are limitations in family history assessment. Moreover, many of the risk models only assess risk for alterations in BRCA and not for more moderate risk or less penetrant genes.


Combined BRAF/MEK inhibition with cetuximab for progressive RAS wild-type BRAF mutated metastatic colorectal cancer

For patients with RAS wild-type metastatic colorectal cancer (mCRC) and a BRAF V600E mutation (BRAF mut), resistance to epidermal growth factor receptor (EGFR)-targeted agents may be overcome with BRAF inhibitors, but combined inhibition of BRAF and EGFR has been only modestly effective. In the phase III BEACON trial, patients with progressive RAS wild-type, BRAF mut mCRC who were randomly assigned to cetuximab plus the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib had longer median overall survival and higher response rates than did those who received cetuximab plus encorafenib, or cetuximab plus irinotecan, and toxicity rates were roughly comparable [3]. These data establish dual inhibition of BRAF and MEK in conjunction with an EGFR inhibitor as an effective strategy to overcome EGFR inhibitor resistance in BRAF mut RAS wild-type mCRC.


Gait speed and grip strength in patients with blood cancers

Older patients with cancer are at increased risks for complications from their disease and its treatments. Various measures have been evaluated to help quantify this risk. In one study of over 300 adult patients aged >=75 years with blood cancers, lower gait speeds were associated with higher mortality, odds of unplanned hospitalizations, and emergency room visits, after adjustment for other clinical and disease factors [4]. Decreases in grip strength were associated with worse survival, but not hospital or emergency room use. Further investigation is needed on the optimal physical assessments to identify older patients with cancer at highest risk for complications.


Entrectinib in ROS1-positive NSCLC and in NTRK-positive cancers

Genetic alterations in both NTRK and ROS1 drive growth of a small subset of solid tumors, and the NTRK/ROS1 inhibitor entrectinib has shown promising activity for such cancers. In a pooled analysis of three trials evaluating entrectinib, the response rate was approximately 80 percent among 51 adult patients with ROS1-positive non-small cell lung cancer (NSCLC), with a median progression-free survival (PFS) of 19 months [5]. Five of seven patients with central nervous system disease had an intracranial response. Among 54 adult patients with solid tumors with an NTRK gene fusion, the response rate was almost 60 percent, with a median PFS of 11 months.


These results led to approval by the US Food and Drug Administration (FDA) for entrectinib in adult patients with ROS1-positive NSCLC [6]. We agree with its use in this setting, but note that the earlier generation ROS1 inhibitor crizotinib remains another appropriate option for ROS1-positive NSCLC, if brain metastases are absent. Entrectinib was also approved for patients >=12 years with NTRK-positive solid tumors without other satisfactory options, if a known resistance mutation in NTRK is not present. We consider both entrectinib and larotrectinib, another NTRK inhibitor, appropriate in this setting.


1. US Preventive Services Task Force, Owens DK, Davidson KW, et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2019; 322:652.


2. Nelson HD, Pappas M, Cantor A, et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2019; 322:666.


3. Kopetz S, Grothey A, Van Cutsem E, et al. BEACON CRC: a randomized, 3-Arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E-mutant metastatic colorectal cancer (LABA06). Abstract available online at (Accessed on July 15, 2019).


4. Liu MA, DuMontier C, Murillo A, et al. Gait speed, grip strength, and clinical outcomes in older patients with hematologic malignancies. Blood 2019; 134:374.


5. Siena S, Doebele RC, Shaw AT, et al. Efficacy of entrectinib in patients (pts) with solid tumors and central nervous system (CNS) metastases: Integrated analysis from three clinical trials. J Clin Oncol 2019; 37S: ASCO abstract #3017.


6. Entrectinib capsules, for oral use. United States Prescribing Information. US National Library of Medicine. (Accessed on September 13, 2019).


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