Finding Waldo: The Evolving Paradigm of Circulating Tumor DNA (ctDNA)-Guided Minimal Residual Disease (MRD) Assessment in Colorectal Cancer (CRC).

Circulating tumor DNA (ctDNA), the tumor-derived cell-free DNA fragments in the bloodstream carrying tumor-specific genetic and epigenetic alterations, represents an emerging novel tool for minimal residual disease (MRD) assessment in patients with resected colorectal cancer (CRC). For many decades, precise risk-stratification following curative-intent colorectal surgery has remained an enduring challenge. The current risk stratification strategy relies on clinicopathologic characteristics of the tumors that lacks precision and results in over-and undertreatment in a significant proportion of patients. Consequently, a biomarker that can reliably identify patients harboring MRD would be of critical importance in refining patient selection for adjuvant therapy. Several prospective cohort studies have provided compelling data suggesting that ctDNA could be a robust biomarker for MRD that outperforms all existing clinicopathologic criteria. Numerous clinical trials are currently underway to validate the ctDNA-guided MRD assessment and adjuvant treatment strategies. Once validated, the ctDNA technology will likely transform the adjuvant therapy paradigm of colorectal cancer, supporting ctDNA-guided treatment escalation and de-escalation. The current article presents a comprehensive overview of the published studies supporting the utility of ctDNA for MRD assessment in patients with CRC. We also discuss ongoing ctDNA-guided adjuvant clinical trials that will likely shape future adjuvant therapy strategies for patients with CRC.

Patterns of Failure and the Need for Biliary Intervention in Resected Biliary Tract Cancers After Chemoradiation.

BACKGROUND: This study assessed patterns of failure and rates of subsequent biliary intervention among patients with resected biliary tract cancers (BTCs) including gallbladder carcinoma (GBC) and extra- and intrahepatic cholangiocarcinoma (eCCA and iCCA) treated with adjuvant chemoradiation therapy (CRT). METHODS: In this single-institution retrospective analysis of 80 patients who had GBC (n = 29), eCCA (n = 43), or iCCA (n = 8) treated with curative-intent resection and adjuvant CRT from 2007 to 2017, the median radiation dose was 50.4 Gy (range 36-65 Gy) with concurrent 5-fluorouracil (5-FU) chemotherapy. All but two of the patients received adjuvant chemotherapy. The 2-year locoregional failure (LRF), 2-year recurrence-free survival (RFS), and 2-year overall survival (OS), and univariate predictors of LRF, RFS, and OS were calculated for the entire cohort and for a subgroup excluding patients with iCCA (n = 72). The predictors of biliary interventions also were assessed. RESULTS: Of the 80 patients (median follow-up period, 30.5 months; median OS, 33.9 months), 54.4% had American Joint Committee on Cancer (AJCC) stage 1 or 2 disease, 57.1% were lymph node-positive, and 66.3% underwent margin-negative resection. For the entire cohort, 2-year LRF was 23.8%, 2-year RFS was  43.7%, and 2-year OS was 62.1%.  When patients with iCCA were excluded, the 2-year LRF was 22.6%, the 2-year RFS was 43.9%, and the 2-year OS was 59.2%. In the overall and subgroup univariate analyses, lymph node positivity was associated with greater LRF, whereas resection margin was not. Biliary intervention was required for 12 (63.2%) of the 19 patients with LRF versus 11 (18%) of the 61 patients without LRF (P < 0.001). Of the 12 patients with LRF who required biliary intervention, 4 died of biliary complications. CONCLUSIONS: The LRF rates remained significant despite adjuvant CRT. Lymph node positivity may be associated with increased risk of LRF. Positive margins were not associated with greater LRF, suggesting that CRT may mitigate LRF risk for this group. An association between LRF and higher rates of subsequent biliary interventions was observed, which may yield significant morbidity. Novel strategies to decrease the rates of LRF should be considered.

Predictors of Resectability and Survival in Patients With Borderline and Locally Advanced Pancreatic Cancer who Underwent Neoadjuvant Treatment With FOLFIRINOX.

OBJECTIVE: The aim of this study was to determine (1) whether preoperative factors can predict resectability of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant FOLFIRINOX, (2) which patients might benefit from adjuvant therapy, and (3) survival differences between resected BR/LA patients who received neoadjuvant FOLFIRINOX and upfront resected patients. BACKGROUND: Patients with BR/LA PDAC are often treated with FOLFIRINOX to obtain a margin-negative resection, yet selection of patients for resection remains challenging. METHODS: Clinicopathologic data of PDAC patients surgically explored between 04/2011-11/2016 in a single institution were retrospectively collected. RESULTS: Following neoadjuvant FOLFIRINOX, 141 patients were surgically explored (BR: 49%, LA: 51%) and 110 (78%) were resected. Resected patients had lower preoperative CA 19-9 levels (21 vs 40 U/mL, P = 0.03) and smaller tumors on preoperative computed tomography (CT) scan (2.3 vs 3.0 cm, P = 0.03), but no predictors of resectability were identified. Median overall survival (OS) was 34.2 months from diagnosis for all FOLFIRINOX patients and 37.7 months for resected patients. Among resected patients, preoperative CA 19-9 >100 U/mL and >8 months between diagnosis and surgery predicted a shorter postoperative disease-free survival (DFS); Charlson comorbidity index >1, preoperative CA 19-9 >100 U/mL and tumor size (>3.0 cm on CT or >2.5 cm on pathology) predicted decreased OS. DFS and OS were significantly better for BR/LA PDAC patients treated with neoadjuvant FOLFIRINOX compared with upfront resected patients (DFS: 29.1 vs 13.7, P < 0.001; OS: 37.7 vs 25.1 months from diagnosis, P = 0.01). CONCLUSION: BR/LA PDAC patients with no progression on neoadjuvant FOLFIRINOX should be offered surgical exploration. Except size, traditional pathological parameters fail to predict survival among resected FOLFIRINOX patients. Resected FOLFIRINOX patients have survival that appears to be superior than that of resectable patients who go directly to surgery.

The Relationship Between Guideline-Recommended Initiation of Therapy, Outcomes, and Cost for Patients with Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: Guideline-recommended therapy for metastatic non-small cell lung cancer (mNSCLC) encourages evidence-based treatment; however, there is a knowledge gap regarding the influence of guideline-recommended initiation of therapy on outcomes and cost. OBJECTIVE: To investigate if lack of guideline-recommended initiation of first-line systemic therapy was associated with worse patient outcomes and increased costs for patients with mNSCLC. METHODS: In this retrospective analysis, 1,344 Medicare patients with mNSCLC were identified from Humana data. Performance status (PS) was imputed using procedure, diagnosis, and durable medical equipment codes pre-index. Guideline-recommended initiation of therapy was defined as ≥1 cycle of National Comprehensive Cancer Network-recommended first-line therapy based on age and PS or targeted therapies regardless of age and PS. Demographics and clinical characteristics were compared by guideline-recommended initiation of therapy. A Cox model assessed factors associated with 6-month mortality. End-of-life quality of care indicators included hospital admission and oncology infusions 30 days preceding death and were evaluated using logistic regression models. A generalized linear model assessed the relationship between guideline-recommended initiation of therapy and total health care costs in the 6 months post-index controlling for clinical, demographic, and treatment characteristics. Logistic models for inpatient stays and emergency department visits were also evaluated. RESULTS: Guideline-recommended therapy initiation was observed in 75.5% of patients. Patients not initiating guideline-recommended therapy were older, with a mean (SD) age of 72.5 (6.7) versus 71.2 (6.2) years (P = 0.001), and more frequently identified as having a low-income subsidy (30.0% vs. 16.4%; P < 0.001). Among the 24.6% of patients who died ≤ 6 months post-index, a greater percentage had not initiated guideline-recommended therapy (28.8% vs. 23.2%; P = 0.040). In adjusted models, PS (not initiation of guideline-recommended therapy) was predictive of mortality (patients with poor PS had an 84% higher probability of death [P = 0.014]). Among decedents, 64.2% were hospitalized, and 33.9% had an oncology-related infusion within 30 days of death, with no differences by guideline-recommended initiation of therapy. These end-of-life quality indicators were not associated with guideline-recommended initiation of therapy in adjusted models. Overall, 47.5% of patients who initiated guideline-recommended therapy were hospitalized compared with 55.0% of patients who did not (P = 0.026). Patients initiating guideline-recommended therapy had higher post-index total and oncology-related health care costs and fewer hospitalizations. In models, these differences in costs and hospitalizations were not associated with initiation of guideline-recommended therapy. CONCLUSIONS: Most patients initiated guideline-recommended therapy, with no differences in mortality and quality of care at the end of life by guideline-recommended initiation of therapy, though adherence beyond treatment initiation was not assessed. Unadjusted hospitalization rates were lower and costs were higher for patients who initiated guideline-recommended therapy. These differences were no longer observed after risk adjustment, suggesting that they may have been influenced by patient characteristics, disease progression, and subsequent treatment decisions. DISCLOSURES: This study was sponsored by Genentech. Khoury, Michael, Parikh, and Bunce are employed by Genentech. Casebeer, Drzayich Antol, DeClue, Hopson, Li, and Stemkowski are employed by Comprehensive Health Insights, Humana, which was contracted by Genentech to conduct this study. Sehman is employed by Humana. Based on this research, 2 posters were presented at the Academy of Managed Care Pharmacy Nexus 2017 on October 16-19, 2017, in Dallas, Texas. Another poster was also presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Annual European Congress on October 29-November 2, 2016, in Vienna, Austria.

Medical Oncologists' Experiences in Using Genomic Testing for Lung and Colorectal Cancer Care.

PURPOSE: Genomic testing improves outcomes for many at-risk individuals and patients with cancer; however, little is known about how genomic testing for non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) is used in clinical practice. PATIENTS AND METHODS: In 2012 to 2013, we surveyed medical oncologists who care for patients in diverse practice and health care settings across the United States about their use of guideline- and non-guideline-endorsed genetic tests. Multivariable regression models identified factors that are associated with greater test use. RESULTS: Of oncologists, 337 completed the survey (participation rate, 53%). Oncologists reported higher use of guideline-endorsed tests (eg, KRAS for CRC; EGFR for NSCLC) than non-guideline-endorsed tests (eg, Onco typeDX Colon; ERCC1 for NSCLC). Many oncologists reported having no patients with CRC who had mismatch repair and/or microsatellite instability (24%) or germline Lynch syndrome (32%) testing, and no patients with NSCLC who had ALK testing (11%). Of oncologists, 32% reported that five or fewer patients had KRAS and EGFR testing for CRC and NSCLC, respectively. Oncologists, rather than pathologists or surgeons, ordered the vast majority of tests. In multivariable analyses, fewer patients in nonprofit integrated health care delivery systems underwent testing than did patients in hospital or office-based single-specialty group settings (all P < .05). High patient volume and patient requests (CRC only) were also associated with higher test use (all P < .05). CONCLUSION: Genomic test use for CRC and NSCLC varies by test and practice characteristics. Research in specific clinical contexts is needed to determine whether the observed variation reflects appropriate or inappropriate care. One potential way to reduce unwanted variation would be to offer widespread reflexive testing by pathology for guideline-endorsed predictive somatic tests.

Prolonged Response to HER2-Directed Therapy in a Patient With HER2-Amplified, Rapidly Progressive Metastatic Colorectal Cancer.

HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers (mCRCs). HER2-targeted therapy is not standard of care, although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2-activating mutations may benefit from HER2-directed therapy. HER2 amplifications and activating mutations have also been implicated in resistance to anti-epidermal growth factor receptor-based therapy. This report describes a patient with KRAS, NRAS, and BRAF wild-type mCRC who experienced disease progression on first-line treatment with FOLFIRI and cetuximab after only 5 months, and subsequently experienced progression on second-line treatment with capecitabine and oxaliplatin plus bevacizumab after 2 months with significant functional decline. Next-generation sequencing of the primary tumor identified HER2 amplification, and we were able to obtain trastuzumab-DM1 for off-label use. The patient had symptomatic clinical benefit from trastuzumab-DM1 and had radiographic disease control for 7 months. On progression, therapy was changed to trastuzumab and pertuzumab, but the patient's disease progressed 3 months later. Treatment with the trastuzumab-DM1 resulted in a sustained response that was longer than his prior responses in the first and second lines of treatment, with a dramatic improvement in the patient's functional status. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-amplifed CRC with trastuzumab-DM1. Clinical trials targeting patients with HER2-mutated and -amplified metastatic colon cancer are currently underway. Molecular insights from investigating HER2 activation and the impact of HER2-directed therapies in a wide variety of solid tumors will create the needed evidence base to more broadly inform patient care.